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£EPA
EPA/600/R-10/095A
September 2010
External Review Draft
Lymphohematopoietic Cancers Induced by Chemicals and
Other Agents: Overview and Implications for Risk
Assessment
NOTICE
THIS DOCUMENT IS AN EXTERNAL REVIEW DRAFT. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be construed to
represent Agency Policy. It is being circulated for comment on its technical accuracy and policy
implications.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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DISCLAIMER
This document is a preliminary draft for review purposes only. This information is
distributed solely for the purpose of pre-dissemination peer review under applicable information
quality guidelines. It has not been formally disseminated by the EPA. It does not represent and
should not be construed to represent any Agency determination or policy. Mention of trade
names or commercial products does not constitute endorsement or recommendation for use.
ABSTRACT
The objective of this report is to provide an overview of the types and mechanisms
underlying the lymphohematopoietic cancers induced by chemical agents and radiation in
humans, with a primary emphasis on leukemia and leukemia-inducing agents. Following a brief
discussion of hematopoiesis and leukemogenesis, a review of the major classes of leukemia-
inducing agents—radiation, chemotherapeutic alkylating agents, and topoisomerase II
inhibitors—is presented along with information on the mechanisms by which these leukemias
occur. This information is then compared with similar information for selected environmental
and occupational leukemia-inducing agents. The last section focuses on how mechanistic
information on human leukemia-inducing agents can be used to better inform risk assessment
decisions. It is evident that there are different types of leukemia-inducing agents that act through
different mechanisms. Even though most have a mutagenic mode of action, leukemia-inducing
agents have different potencies and associated risks, which appear to be significantly influenced
by the specific mechanisms involved in leukemogenesis. Identifying the specific types of
cancer-causing agents with their associated mechanisms and using this information to inform key
steps in the risk assessment process remains one of the ongoing challenges for research and
regulatory scientists.
This document is a draft for review purposes only and does not constitute Agency policy.
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CONTENTS
LIST OF TABLES v
LIST OF FIGURES vi
LIST 01 ABBREVIATIONS vii
PREFACE viii
AUTHORS, CONTRIBUTORS, AND REVIEWERS ix
EXECUTIVE SUMMARY xi
1. INTRODUCTION TO LYMPHOHEMATOPOIETIC CANCERS 1
1.1. OVERALL INCIDENCE AM) TRENDS 3
2. HEMATOPOIESIS 5
3. ORIGINS OF LYMPHOHEMATOPOIETIC NEOPLASIA 8
4. LEUKEMIA- AND I.YY1PI IOMA-INDl CING AGENTS 11
5. OVERVIEW OF THE MAJOR CLASSES OF LEUKEMIA-INDUCING AGENTS 13
5.1. IONIZING RADIATION 13
5.2. CHEMOTHERAPEUTIC AGENTS 14
5.2.1. Alkylating Agent-Related Leukemias 15
5.2.2. Topoisomerase II Inhibitor-Related Leukemias 16
5.2.3. Other Likely Leukemia-Inducing Therapeutic Agents 19
6. MECHANISMS INVOLVED IN t-AML 21
7. FACTORS CONFERRING AN INCREASED RISK OF INDUCED LEUKEMIA 24
7.1. MYELOSUPPRESSION AND IY1Y11 NOTOXKTI Y 24
7.2. GENETIC POLYMORPHISMS 25
8. EXAMPLES OF SPECIFIC LEUKEMIA-INDUCING CHEMICALS 29
8.1. MELPHALAN 29
8.2. ETHYLENE OXIDE 30
8.3. 1,3-BUTADIENE 32
8.4. FORMALDEHYDE 35
9. RISK ASSESSMENT IMPLICATIONS 37
9.1. HAZARD IDENTIFICATION 37
9.1.1. Utility of Short-Term Genotoxicity Tests 38
9.1.2. Usefulness of Animal Bioassays 39
9.1.3. Combining Different Types of Lymphohematopoietic Cancers for Analysis... 40
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CONTENTS (continued)
9.1.4. Potential Influence of Latency Period in Identifying Leukemogens 42
9.1.5. Metabolism and Bioactive Dose at the Target Organ 43
9.1.6. DNA-Adduct Type, Metabolism, and Repair 44
9.1.7. Individual Susceptibility 45
9.1.8. Summary 46
REFERENCES 70
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LIST OF TABLES
Table 1. Simplified classification of the major lymphohematopoietic neoplastic diseases in
humans based largely on the French-American-British (FAB) classification 47
Table 2. WHO classification of myeloid and related neoplasms 49
Table 3. WHO classification of lymphoid neoplasms 51
Table 4. Cytogenetic comparisons of de novo leukemias and t-AML 54
Table 5. Frequency of molecular mutations in de wovoAMLand t-MDS/t-AML 56
Table 6. Gene mutations observed in the Copenhagen series of 140 patients with t-MDS
(ii = 89) or t-AML (n 5 1) 57
Table 7. Characteristics of selected known and probable human leukemia- and lymphoma-
inducing agents 58
Table 8. Likely mechanisms involved in the carcinogenesis of selected known and probable
human leukemia- and lymphoma-inducing agents 61
Table 9. General characteristics of human leukemias and related neoplasms induced by
recognized leukemia-inducing agents 66
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LIST OF FIGURES
Figure 1. Simplified model of hematopoiesis showing lineages of major types of hematopoietic
cells 67
Figure 2. Hierarchical stem cell origins of leukemia and related cancers 68
Figure 3. Genetic pathways of t-MDS and t-AML based on 140 cases from the Copenhagen
study group 69
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LIST OF ABBREVIATIONS
ALL
acute lymphoblastic leukemia
AML
acute myeloid leukemia
ANLL
acute nonlymphocytic leukemias
BEIR
Biological Effects of Ionizing Radiation
CLL
chronic lymphocytic leukemia
CML
chronic myeloid leukemia
EMS
ethyl methane sulfonate
ENU
A-nitroso-A'-ethylurea
FAB
French-American-British
IARC
International Agency for Research on Cancer
MDS
myelodysplastic syndromes
MM
multiple myeloma
NCI
National Cancer Institute
NHL
non-Hodgkin lymphoma
NK
natural killer
NQOl
NADPH quinone oxidoreductase 1
SCE
sister chromatid exchange
SEER
Surveillance Epidemiology and End Results
t-AML
karyotypes of patients who have developed leukemia following therapy
TMPT
thiopurine methyltransferase
UNSCEAR
United Nations Scientific Committee on the Effects of Atomic Radiation
WHO
World Health Organization
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PREFACE
This report represents the update and expansion of two earlier U.S. Environmental
Protection Agency (EPA) documents entitled "Chemical and Radiation Leukemogenesis in
Humans and Rodents and the Value of Rodent Models for Assessing Risks of
Lymphohematopoietic Cancers" (EPA/600/R-97/090, May 1997). This report provides an
overview of chemically-induced leukemias and lymphomas and is intended to provide insights
into how mechanistic information on leukemia-inducing agents can be used to assess risks from
leukemia-inducing agents.
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
PROJECT MANAGER AND CONTRIBUTORS
Nagalakshmi Keshava, Ph.D.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
Babasaheb Sonawane, Ph.D.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
AUTHOR
David A. Eastmond, Ph.D.
University of California, Riverside
Riverside, CA 92507
REVIEWERS
George Woodall, Ph.D.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC
Maureen Gwinn, Ph.D.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
Glinda Cooper, Ph.D.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (continued)
Jennifer Jinot, Ph.D.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
Cheryl Scott, M.S.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
Chao Chen, Ph.D.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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EXECUTIVE SUMMARY
Lymphohematopoietic neoplasias represent a heterogeneous group of clonal
hematopoietic and lymphoid cell disorders and are one of the most common types of cancer
induced by environmental and therapeutic agents. The objective of this report is to provide an
overview of the types and mechanisms underlying the lymphohematopoietic cancers induced by
chemical agents and radiation in humans, with a primary emphasis on leukemia and leukemia-
inducing agents. Following a brief discussion of hematopoiesis and leukemogenesis, a review of
the major classes of leukemia-inducing agents—radiation, chemotherapeutic alkylating agents,
and topoisomerase II inhibitors—is presented along with information on the mechanisms by
which these leukemias occur. This information is then compared with similar information for
selected environmental and occupational leukemia-inducing agents. The last section focuses on
how mechanistic information on human leukemia-inducing agents can be used to better inform
risk assessment decisions. A brief overview of the major points in the report is presented below.
It is widely recognized that lymphohematopoietic neoplasms originate through multi-step
processes involving a series of genetic and epigenetic alterations that transform a normal
hematopoietic or lymphoid cell into a malignant tumor. The various lymphohematopoietic
cancers are believed to originate in specific types of pluripotent or lineage restricted cells at
different stages in hematopoiesis and immune cell development. Current evidence indicates that
the acute and chronic myeloid leukemias (CMLs) as well as precursor lymphomas, the acute
lymphoblastic leukemias (ALL) - B lymphoblastic leukemia/lymphoma and T lymphoblastic
leukemia/lymphoma originate in hematopoietic stem or progenitor cells; whereas, other
lymphomas and chronic lymphocytic leukemia (CLL) have their origins in mature lymphoid
cells. This information on the origin of these cancers as well as morphologic, cytochemical and
immunophenotypic features of the neoplastic cells provide valuable information for grouping
various lymphohematopoietic cancers and for identifying the cell types targeted by carcinogenic
agents.
Lymphohematopoietic neoplasia represents one of the most common cancers induced by
chemical, physical, and infectious agents. To date, the International Agency for Research on Cancer
(IARC) has identified over 100 agents as human carcinogens. Of these, approximately 25% have been
shown to induce either leukemias or lymphomas in humans. Many of these are antineoplastic drugs, but
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a variety of other agents including industrial chemicals, various forms of radiation, immunosuppressive
drugs, and infectious agents have also been shown to induce lymphohematopoietic cancers in humans.
In evaluating the different types of induced leukemias and lymphomas, a number of general patterns
become apparent. Leukemias are the primary type of cancer induced by chemical agents. Most of these
are acute nonlymphocytic leukemias (ANLLs, synonymous with acute myeloid leukemia [AML]) with
relatively short median latency periods and are formed through the induction of mutations affecting
critical cancer-related genes. Radiation, which is also thought to act through a mutagenic mode of
action, is frequently associated with ANLL as well as CML and ALL.
Exposure to a variety of infectious agents is causally related to the formation of lymphoid
neoplasms. The induced lymphomas identified to date appear to be primarily associated with
chronic infection with either viruses or Helicobacter bacteria, agents that are
immunomodulating, and/or specifically target lymphoid cells. Two chemical agents,
cyclosporine and azathioprine, which are associated with the development of non-Hodgkin
lymphoma (NHL) are also strongly immunosuppressive, and this immunosuppression is believed
to play a critical role in the development of the associated lymphomas.
Among the induced leukemias, different subtypes with particular characteristics have
shown to be induced by different classes of agents. For example, the alkylating agent class of
chemotherapeutic agents typically induces acute myeloblastic leukemias that are often preceded
by a myelodysplastic phase and are characterized by loss of all or part of chromosomes 5 or 7.
These leukemias generally develop with a median latency period of 5-7 years from the
beginning of treatment. In contrast, the leukemias induced by the epipodophyllotoxin class of
topoisomerase II inhibitors develop much sooner with a median latency period of 2-3 years.
These leukemias are typically characterized as monocytic or myelomonocytic subtypes and
exhibit reciprocal translocations involving a specific region on the long arm of chromosome 11
(1 lq23). While much less is known about leukemias and lymphomas induced by environmental
agents such as ethylene oxide and 1,3-butadiene, the types of neoplasms causally associated with
these agents appear to differ substantially from those described above and suggest that these
agents belong to a separate class of carcinogenic agent.
The last section of the report discusses how mechanistic information on human leukemia-
inducing agents can be used to better assess the risks from exposure to environmental chemicals.
A range of topics is considered including brief discussions on the usefulness of short-term and
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animal bioassays, the combining of various tumor types for analysis, the impact of latency
periods on the detection of leukemias, and the modifying influences of metabolism,
pharmacokinetics, DNA-adduct type and repair, as well as individual susceptibility factors in
assessing the risks associated with leukemia-inducing agents
In conclusion, it is evident that there are different types of leukemia-inducing agents that
act through different mechanisms. Even though most have a mutagenic mode of action,
leukemia-inducing agents have different potencies and associated risks, which appear to be
significantly influenced by the specific mechanisms involved in leukemogenesis. Identifying
the specific types of cancer-causing agents with their associated mechanisms and using this
information to inform key steps in the risk assessment process remains one of the ongoing
challenges for research and regulatory scientists. For the alkylating agent class of carcinogens,
an approach such as that described by Vogel and colleagues (Vogel et al., 1998) supplemented
with more recent genomic, proteomic, and biomarker information would appear to present a
reasonable and scientifically valid step towards this objective.
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1. INTRODUCTION TO LYMPHOHEMATOPOIETIC CANCERS
Lymphohematopoietic neoplasia can be described as an uncontrolled proliferation or
expansion of hematopoietic and lymphoid cells that are unable to differentiate normally to form
mature blood cells (Sawyerset al., 1991). These neoplasms represent clonal expansions of
hematopoietic cells, almost always within either the myeloid or lymphoid lineage (Nowell, 1991;
WHO, 2008). Infrequently, some leukemias exhibit both myeloid and lymphoid characteristics
and are known as biphenotypic leukemias (Russell, 1997). The myeloid clones are designated as
chronic or acute leukemias, depending upon the rate of clonal expansion and the stage of
differentiation that dominates the leukemic clone. Lymphoid neoplasms typically manifest
themselves in the blood as chronic or acute lymphoblastic leukemias or remain confined to
lymphoid proliferative sites such as the lymph nodes or spleen and are designated as lymphomas
(Nowell, 1991). Acute leukemias tend to have a rapid onset with a predominance of immature
cells whereas chronic leukemias have a more insidious onset and progress over a period of
months or years to a blast or acute leukemic phase.
Using this basic classification, leukemias can be described as one of four major types—
acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic
leukemia (CLL), and chronic myeloid leukemia (CML). Similarly, lymphomas are broadly
classified as Hodgkin or non-Hodgkin lymphomas (NHL) depending upon the appearance of a
specific cancer cell type, the Reed-Sternberg cell, which is found in Hodgkin lymphomas (ACS,
2009). Within these larger groupings, there are numerous subtypes involving specific cells that
have unique characteristics, origins, and increasingly recognized clinical significance. These
subtypes are generally classified according to morphologic, cytogenetic, immunophenotypic, and
more recently, molecular characteristics according to the French-American-British (FAB) or
World Health Organization (WHO) classification systems (Head and Pui, 1999; WHO, 2001,
2008; Haferlachet al., 2005). For convenience, a simplified classification scheme for the
leukemias and lymphomas based largely on the FAB classification system (shown in Table 1
[Sullivan, 1993]) will be the basis for most descriptions used in this document. A more thorough
and complicated classification of the primary types and subtypes of lymphohematopoietic
diseases based on the most recent WHO classification (WHO, 2008; Vardiman et al., 2009) is
shown in Tables 2 and 3 for myeloid and lymphoid neoplasms, respectively. It should be noted
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that in the more recent WHO classifications (IARC, 2008c), lymphocytic leukemias and
lymphomas are no longer considered to be different diseases and should be evaluated
accordingly. However, for simplicity and due to the difficulties involved in reclassifying
neoplasms based on studies that were conducted many years ago, the classifications used in the
original studies or in the IARC monographs will be used in this document. It should be
recognized, however, that considerable heterogeneity exists among NHL subtypes as classified
according to older classification systems (Morton et al., 2007). In addition, the older schemes do
not consider temporal changes in classifying distinct variants of NHL. For example, lymphomas
of mucosa-associated lymphoid tissues (MALT) and mantle cell lymphoma as classified by
WHO (2008), were previously considered as either pseudolymphomas or benign lympoid
disorders. Similarly, some forms of T-cell lymphomas and aplastic large-cell lymphomas were
earlier classified as Hodgkin's disease (Banks, 1992)
Among the leukemias, the two major diagnostic categories, ALL and AML, can be
further classified based upon cellular features. ALL is subdivided by FAB morphology (LI, L2,
and L3) and by immunophenotype (B-cell, early pre-B, pre-B, and T-cell) (Bhatiaet al., 1999).
AML is classified primarily by morphological characteristics into eight different FAB subgroups
(M0-M7) based upon the myeloid lineage and degree of maturation involved. Similarly, the
myelodysplastic syndromes (MDSs), a series of blood disorders characterized by maturation
defects resulting in ineffective hematopoiesis, have also been classified by the FAB and WHO
systems (see Tables 1 and 2, respectively). These are commonly considered to be preleukemic
because a variable, but significant, proportion (1 to 33%) of the various disorders progress to
frank leukemia (Wright, 1995; WHO, 2001, 2008; Hasleet al., 2003).
The objective of this article is to provide an overview of the types of
lymphohematopoietic neoplasia induced by chemical agents and radiation in humans, and to
summarize current information on the mechanisms of chemical leukemogenesis. Much of the
discussion focuses on myeloid neoplasms due to the evolving knowledge of lymphomas that is
only now integrated into ongoing epidemiological and clinical studies. An overview of the major
classes of leukemia-inducing agents—radiation, the alkylating agents, and topoisomerase II
inhibitors—will then be presented followed by examples of environmental and occupational
leukemia-inducing agents and a brief discussion of factors influencing chemical leukemogenesis.
Lastly, the article will end with a discussion of how mechanistic information on human
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leukemia-inducing agents can be used to better assess the risks from exposure to environmental
chemicals.
1.1. OVERALL INCIDENCE AND TRENDS
Lymphohematopoietic neoplasms are an uncommon, yet significant, cause of cancer-
related deaths. In 2009, it was estimated that leukemia would be diagnosed in 44,790 people in
the United States (ACS, 2009). Slightly over half of these will be chronic leukemias (20,540)
with the remainder being acute leukemias (18,570) and others that have not been clearly
identified (5,680). Because of the limitations of current therapies, leukemia represents the 5th
leading cause of cancer deaths among males in the United States and the 7th leading cause among
females (ACS, 2009). Furthermore, it was estimated that 74,490 new cases of lymphoma would
be diagnosed in the United States in 2009 (ACS, 2009). Of these, 89% (65,980 cases) were
estimated to have been NHL and 11% Hodgkin lymphoma (8,510 cases). NHL represents the 9th
leading cause of cancer-related deaths in males and the 6th in females. It should be noted that
more recent cancer incidence and mortality data can be obtained from the National Cancer
Institute (NCI)'s Surveillance Epidemiology and End Results (SEER) Web site
(http:// seer. cancer, gov/ stati sties/).
While leukemia occurs much more commonly in adults than in children, childhood
leukemia still accounts for approximately 30% of all childhood cancers in the United States and
is a leading cause of disease-related death among children (Smithet al., 2005; ACS, 2006). The
incidence of leukemia in children (36 per million) is similar to that seen in young to middle-aged
adults (ages 20-44) but roughly one-tenth of that of adults aged 45 years and older, where the
annual incidences increase with age from 144 to 545 per million (Xieet al., 2003; ACS, 2006).
In adults, roughly 85% of the leukemias are myeloid in origin with the remainder being
lymphoid (Greaves, 1999). In children, the opposite occurs with 80% of the leukemias
originating from lymphoid cells. Moreover, the incidence trends for adult and pediatric
leukemias differ substantially. While the overall trend for adult leukemia has generally declined
with time, the incidence of childhood leukemias has increased noticeably in recent years, largely
due to an increase of ALL and AML in children that has increased by 1.1 and 0.5% per year,
respectively (Xieet al., 2003). Similar increases have been seen across Europe and in other
developed countries (Hrusaket al., 2002; Steliarova-Foucheret al., 2004). Fortunately, there has
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1 been significant progress in treating childhood leukemias so that the 5-year survival rate for the
2 affected children is now approximately 80% (ACS, 2006). The survival rate for adult leukemias
3 varies by type with 5-year survival rates of 22% for AML patients, 66% for ALL patients, and
4 76% for CLL patients (ACS, 2009).
5
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2. HEMATOPOIESIS
Hematopoiesis is the process by which the cells of the blood are formed. The
development of the hematopoietic system begins in several mesodermal lineages in the
mammalian conceptus with cells migrating from the primitive streak to three blood-forming
tissues: the yolk sac, the para-aortic splanchnopleura/aora-gonadal-mesonephros region, and the
chorio-allantoic placenta (for review, see Dzierzak and Speck [2008]). Hematopoietic stem cells
capable of conferring complete long-term and multi-lineage repopulation of hematopoiesis in
irradiated adult recipient mice appear in the aorta-gonadal-mesonephros and other tissues during
the middle of embryogenesis (Embryonic Day 10.5 in the mouse). These cells proceed to
colonize the liver, then the thymus, spleen, and bone marrow (by Embryonic Day 15 in the
mouse) where hematopoiesis primarily occurs after birth.
The formation of blood cells originates with the hematopoietic stem cell. As described
by Wilson and Trumpp (2008), stem cells are functionally defined as cells that can both self-
renew (maintain their numbers at a constant level) and give rise to all mature cells in the tissue in
which they reside. The formation of blood cells is supported by a small population of pluripotent
stem cells that exhibit the capacity to self-renew and are capable of extensive proliferation.
These cells can also reconstitute all hematopoietic lineages and are capable of long-term
reconstitution of the hematopoietic system of recipient animals. The primitive pluripotent stem
cells are estimated to comprise 1 in 100,000 bone marrow cells and give rise to multipotent and
committed progenitor cells, which represent approximately 2-5 per 1,000 marrow cells (Mihich
and Metcalf, 1995). Each of these progenitor cells can generate 100,000 or more maturing
progeny. The process of proliferation and differentiation is regulated by more than 25 growth
factors, cytokines, and other regulators that may act directly upon one or more of the major
lineages of blood cells or interact to influence cell growth (Mihich and Metcalf, 1995). A
diagram illustrating the relationships between the major cell types involved in hematopoiesis is
shown in Figure 1.
With the exception of lymphocytes where maturation also continues in the thymus,
spleen and peripheral tissues, the formation of blood cells in normal human adults occurs almost
exclusively in the bone marrow. All mature circulating blood cells have a finite life with the
majority of cells being terminally differentiated and unable to replicate (Bagby, 1994). In order
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to maintain steady-state levels, the formation of cells in the marrow must equal the rate of
cellular senescence and elimination. As a result, the hematopoietic system has a tremendous
proliferative capacity with estimates of cell turnover ranging from 130 to 500 billion cells per
day in a 70-kg man (Jandl, 1996; Bryderet al., 2006). In addition, the hematopoietic system in
the central bone marrow helps respond to a variety of environmental stresses and infection by
increasing the blood cell counts of specific lineages when needed (Bagby, 1994; Jaiswal and
Weissman, 2009). For example, upon exposure to a hypoxic environment, erythrocyte
production will increase without a change in the production of neutrophils. Similar lineage-
specific responses are required following exposure to myelotoxic agents. To maintain steady-
state blood cell levels and to respond to environmental pressures, hematopoiesis, of necessity,
must be a highly regulated process. Historically, the responses to infection and environmental
stresses were believed to occur exclusively within the bone marrow. However, as described
below, it has recently been shown that an immune response to infection can occur at
extramedullary sites due to the homing, proliferation, and differentiation of hematopoietic stem
and progenitor cells at these ecotopic sites within the body (Jaiswal and Weissman, 2009;
Schulzet al., 2009).
As indicated above, the hematopoietic stem cells normally reside within the bone
marrow, a tissue with specialized vasculature and shielding that provides an excellent
environment for the development of blood cells (Papayannopoulou and Scadden, 2008). In
addition to their ability to self-renew, primitive pluripotent hematopoietic stem cells give rise to
a number of multipotent progenitor cells, which, in turn, give rise to oligopotent progenitor cells
(see Figure 1 and Bryderet al. [2006]). Among these, the committed lymphoid progenitors give
rise to mature B lymphocytes, T lymphocytes, and natural killer (NK) cells whereas the common
myeloid progenitors give rise to granulocyte-macrophage progenitors (which differentiate into
monocytes/macrophages and granulocytes), and megakaryocyte/erythrocyte progenitors (which
differentiate into megakaryocytes/platelets and erythrocytes). Both the myeloid and lymphoid
progenitor cells have also been proposed to form dendritic cells, which play a role in regulating
the immune system. In addition to these major types of blood cells, a number of the cell types,
for example, the granulocytes can further differentiate into more specialized blood cells such as
neutrophils, eosinophils, and basophils. As a result, the number of unique cell types derived
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from the hematopoietic stem cell is quite large and, as indicated above, the total number of
individual cells formed per day numbers in the hundreds of billions.
Hematopoietic stem and progenitor cells are commonly identified based on the presence
or absence of lineage markers or antigen expression on the cell surface or in the cytoplasm. As
presented by Bryder and associates, the most primitive hematopoietic stem cell identified to date
in humans exhibits the cell surface markers, Lin"CD90+CD38"CD34+ meaning that it is negative
for the lineage differentiation surface antigen Lin, namely B'G'MT" (B220 for B cells, Gr-1 for
granulocytes, Mac-1 for myelomonocytic cells, and CD4 and CD8 for T cells), negative for the
surface antigen CD38 and positive for the surface antigens CD90 and CD34 (Bryderet al., 2006;
Li and Li, 2006). As described by Iwasaki and Akashi (2007) and (Bryderet al., 2006), the
lineage markers and differentiation pathways differ in notable ways between the mouse and the
human.
While hematopoietic stem and progenitor cells normally reside in specialized niches in
the bone marrow, they can be mobilized into the peripheral blood either at low levels
spontaneously or in large numbers as a result of cytokine or chemical treatment (Levesqueet al.,
2007; Schulzet al., 2009). These mobilized cells remain in circulation for only short periods of
time (minutes to hours) before homing to another peripheral tissue or returning to the bone
marrow. As a result, there appears to be a constitutive recirculation of hematopoietic stem and
progenitor cells between the bone marrow, extramedullary tissues, and the lymphoid
compartments (Schulzet al., 2009). Consequently, it is theoretically possible for DNA damage
or other types of potentially leukemogenic alterations to affect hematopoietic stem cells while
they circulate in the blood and extramedullary spaces. Upon exposure to mobilizing agents such
as specific chemokines, toxicants, antibodies, or growth factors, or under conditions of stress or
myelosuppression, large numbers of these stem and progenitor cells can be released into the
peripheral blood (Levesqueet al., 2007). Clinically, these mobilized cells can be harvested for
use in bone marrow transplantation. The natural role of mobilization is not fully known, but
there is evidence that the circulating hematopoietic stem and progenitor cells may help replenish
tissue-residing myeloid cells such as specific monocytes, macrophages, and dendritic cells or
help in rapidly responding to tissue injury and infection (Jaiswal and Weissman, 2009; Schulzet
al., 2009).
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3. ORIGINS OF LYMPHOHEMATOPOIETIC NEOPLASIA
As with other cancers, leukemogenesis and lymphomagenesis are multi-step processes
involving a series of genetic and epigenetic alterations involved in the transformation of a normal
cell into a malignant cell. The various lymphohematopoietic cancers are believed to originate in
specific types of pluripotent or lineage-restricted cells at different stages in hematopoiesis (see
Figure 2; Greaves, 1999). As illustrated in the figure, leukemias and lymphomas can originate
within many types of hematopoietic or hematopoietic-forming cells. With a few rare exceptions,
most leukemias and lymphomas originate at the hematopoietic stem cell stage or at later
progenitor or lineage-restricted stages. For example, most adult leukemias of myeloid origin
(AML, MDS, and CML) as well as adult ALL are believed to originate at the pluripotent stem or
progenitor cell stage whereas childhood leukemias are believed to originate during a subsequent
stage of differentiation at either the lineage-restricted lymphoid or myeloid stem cell stage. For
most types of adult AML, the key leukemic transformations appear to occur in hematopoietic
stem cells (Warneret al., 2004). However, for APL, the key transformative event may occur at
the committed myeloid progenitor stage (Passegueet al., 2003; Warneret al., 2004). For a few
others, such as those possessing the MLL-ENL fusion gene, the transformative event can occur
either at the pluripotent or the committed stem cell stage (Cozzioet al., 2003). In contrast, many
lymphomas (NHL, Hodgkin lymphoma, Burkitt lymphoma) and all myelomas, as well as,
several rare leukemias/lymphomas (adult T-cell leukemia, prolymphocyte leukemia, hairy cell
leukemia) and one common (CLL) leukemia are believed to originate in mature lymphoid
cells(Greaves, 1999; Harriset al., 2001). An understanding of the origin of these cancers can be
useful for grouping various lymphohematopoietic cancers and can provide insight into the cell
types targeted by carcinogenic agents.
Consistent with the multi-step nature of leukemogenesis, over 300 different genetic
alterations and mutations have been identified (Kelly and Gilliland, 2002). Indeed, a recent
examination of alterations affecting the MLL gene, a cancer-related gene located at band 1 lq23,
in pediatric and adult leukemias, identified a total of 87 different rearrangements, primarily
translocations, involving this one gene (Meyeret al., 2006). While most of the detected
alterations are rare, certain translocations and genes are more prevalent and are typically
associated with specific leukemic subtypes (Bhatiaet al., 1999; Greaves and Wiemels, 2003).
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Many of these genetic alterations can only be detected at the molecular level. However, others
have been detected using cytogenetic, molecular cytogenetic and genomic approaches.
Nonrandom chromosomal alterations are detected in the neoplastic cells of a majority of patients
with leukemias or lymphomas, and the identification of genes involved in these alterations has
provided valuable insights into leukemogenesis and lymphomagenesis in humans (Chen and
Sandberg, 2002; Mrozeket al., 2004; Pedersen-Bjergaardet al., 2006; Qianet al., 2009). Because
of their importance, an overview of genetic changes in the development of leukemia is described
below.
Common clonal cytogenetic changes seen in leukemias include alterations in
chromosome number such as loss or gain of one or more chromosomes (e.g., monosomy 7 and
trisomy 8, respectively), balanced and unbalanced chromosome translocations, deletions, or
inversions involving specific chromosomal regions as well as complex arrangements involving
combinations of the above. In some cases, these are a reflection of the genetic instability that is
common in many types of cancers. However in many cases, these are highly specific involving
genes that are directly involved in the cancer process. For example, the translocation between
chromosomes 15 and 17, (t(15;17)(q22;ql2-21)) that is characteristic of the promyelocytic form
of AML (FAB M3), results in a fusion gene involving the PML gene on chromosome 15 and the
retinoic acid receptor alpha (RARa) gene on chromosome 17. This hybrid gene blocks
differentiation of the developing myeloid cells at the promyelocytic stage (Downing, 1999), a
characteristic feature of the disease. As seen in Table 4, significant differences have been seen in
the karyotypes of patients who have developed leukemia following therapy and those who have
no history of exposure to chemotherapy or other leukemogenic agents. The former are called
t-AML and the latter, de novo leukemias.
In addition to these microscopically visible chromosomal alterations, mutations at the
molecular level affecting specific cancer-related genes such as RAS, FTL3, GATA1, and TP53
have also been seen in t-AML and de novo leukemias at varying frequencies (see Table 5). For
example, mutations in genes of the receptor tyrosine kinase/RAS-BRAF signal transduction
pathway are reported to be present in over 50% of de novo AML (Christiansenet al., 2005).
These occur through many mechanisms including base pair substitutions, frame shifts, internal
tandem duplications, gene fusions, and splicing errors (for examples in AMLl, see [Roumieret
al., 2003]). In addition, epigenetic alterations such as changes in the methylation patterns in
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leukemia-related genes or their promoter regions have also been seen in many types of leukemia,
including t-AML (Zhenget al., 2004; Pedersen-Bjergaardet al., 2006; Nerviet al., 2008).
In recent years, researchers have begun to identify patterns among the myriad of
translocations, gene arrangements, and point mutations involved in myeloid leukemias and have
created a model for leukemogenesis (Deguchi and Gilliland, 2002; Kelly and Gilliland, 2002).
According to the model proposed by (Kelly and Gilliland, 2002)
AML is the consequence of collaboration between at least two broad classes of
mutations. Class I mutations, exemplified by constitutively activated tyrosine
kinases or their down stream effectors, such as BCR/ABL, TEL/PDGF|3R,
N-RAS, or K-RAS mutants, or constitutively activated FLT3, confer a
proliferative or survival advantage to hematopoietic cells. When expressed alone,
these mutant genes confer a CML-like disease characterized by leukocytosis with
normal maturation and function of cells. Class II mutations result in loss of
function of transcription factors that are important for normal hematopoietic
differentiation and include the AML1/ETO, CBF|3/SMMHC, PML/RARa, and
NUP98/HOXA9 fusions as well as point mutations in hematopoietic transcription
factors such as AML1 and C/EBPa. These mutations would also be predicted to
impair subsequent apoptosis in cells that do not undergo terminal differentiation.
When expressed alone, these mutations may confer a phenotype like most MDS.
Regardless of the timing or order of acquisition of mutations, individuals who
accrue both Class I and Class II mutations have a clinical phenotype of AML
characterized by a proliferative and/or survival advantage to cells and by impaired
hematopoietic differentiation.
A list of the gene mutations seen in patients with t-MDS or t-AML separated into these two
mutation classes is shown in Table 6.
More recently, additional interrelationships between new and previously identified
genetic alterations, leukemogenic agents, and types of leukemia have been reported
(Christiansen et al., 2001, 2004; Haradaet al., 2003; Zhenget al., 2004; Klymenkoet al., 2005;
Rege-Cambrinet al., 2005; Wiemelset al., 2005). As illustrated by (Pedersen-Bjergaardet al.,
2008), the interactions between these various genes can become quite complicated, and the
outcome of these interactions is not fully understood. It should also be noted that some genes
such as TP53 do not easily fit within this classification scheme, which suggests that other types
of genetic changes are likely to be necessary for the conversion of a normal hematopoietic stem
or progenitor cell into a fully transformed leukemic cell (Pedersen-Bjergaardet al., 2008).
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4. LEUKEMIA- AND LYMPHOMA-INDUCING AGENTS
While most leukemias occur in individuals with no obvious exposure to radiation or
chemical carcinogens (de novo leukemias), a significant number, known as secondary leukemias
develop in individuals who have previously been exposed to radiation, industrial chemicals, or
chemotherapeutic agents. Approximately 40 years ago, the IARC began evaluating chemicals
(and later other types of agents) for their ability to induce cancer in humans. Since 1971, IARC
has evaluated more than 900 agents (including exposure circumstances) and identified more than
100 as being carcinogenic to humans (classified as Group 1: Carcinogenic to Humans\IARC,
2010]). Another 66 have been classified in Group 2A, which indicates agents that are Probably
Carcinogenic to Humans. Among the 100+ agents in Group 1, approximately 25% have been
established as causing a lymphohematopoietic cancer (see Table 7). These include eight
therapeutic drugs or mixtures, five industrial chemicals or contaminants, two immunosuppressive
drugs, six forms of radiation, two occupational or lifestyle exposures, and six infectious agents.
Thus, leukemias and lymphomas represent one of the most common types of cancer induced by a
wide variety of carcinogens. In addition, three other Group 1 carcinogens (see Table 7), which
induce cancer at other sites, are also thought to be likely to induce either a leukemia or
lymphoma. Of the 66 Group 2A agents, there is evidence based either on human studies, animal
bioassays, or structural similarities that at least 10 of these chemicals are also likely to cause
leukemia in humans. Table 7 lists the Group 1 and 2A agents that have been established, or are
likely to cause leukemia or lymphoma, as well some of their characteristics. The same list of
agents with key information related to the likely mechanisms responsible for the
lymphohematopoietic cancers is shown in Table 8.
In examining the information in Tables 7 and 8, a number of general patterns become
apparent. Leukemias are the primary type of cancer induced by the chemical agents, and most of
these are ANLLs (synonymous with AML). These were almost always induced by agents that
are either directly DNA-reactive or that can be metabolized (or otherwise converted) into
DNA-reactive species. Many of the leukemogens are bifunctional alkylating agents; chemicals
that form adducts on DNA bases involved in base-pairing such as the 06 of guanine or induce
chromosomal damage through the inhibition of topoisomerase II. The primary mode of action
for these agents is through the induction of mutations, either gene mutations or chromosomal
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mutations. Consistent with their proposed mutagenic mode of action, most of the leukemia-
inducing agents have been reported to induce structural chromosome aberrations in the
peripheral blood of exposed humans. Myelotoxicity is also commonly seen in humans (and
animals) exposed to these leukemogenic agents. Exposure to radiation in various forms was
frequently associated with ALL and CML, in addition to ANLL. These are also likely due to the
effects of ionizing radiation on DNA, either directly or indirectly, and are believed to occur
through a mutagenic mode of action.
In contrast to these DNA-damaging agents, exposure to a variety of infectious agents is
causally related to the formation of lymphoid neoplasms. The induced lymphomas appear to be
primarily associated with chronic infection with either viruses or Helicobacter bacteria that are
immunomodulating and/or specifically target lymphoid cells. The two chemical agents,
cyclosporine and azathioprine, which also induce NHL, are also strongly immunosuppressive. In
addition, TCDD, which may induce NHL, is also immunosuppressive, so this could be the
mechanism underlying its lymphoma-inducing effects. Although not reviewed by IARC and,
hence, not presented in Tables 7 and 8, autoimmune disorders and other diseases associated with
immune stimulation and inflammation are increasing recognized from large consortia studies as
risk factors for lymphoma (Vajdic et al., 2009, Ekstrom Smedby et al., 2008; Cocco et al., 2008;
Meters et al., 2006).
Similar to the Group 1 agents, the Group 2A leukemogens are associated with the
induction of ANLL. For chemicals for which information is available, these agents are also
myelotoxic and clastogenic and are believed to most likely induce their leukemogenic effects
through a mutagenic mechanism.
In summary, the vast majority of the leukemia-inducing agents are believed to act
through a mutagenic mode of action whereas the lymphoma-inducing agents most likely act
through immunomodulation and related effects. An overview of the major classes of leukemia-
inducing agents is presented below.
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5. OVERVIEW OF THE MAJOR CLASSES OF LEUKEMIA-INDUCING AGENTS
5.1. IONIZING RADIATION
As a result of its widespread medical, military, and energy-related uses, large numbers of
people have been exposed to ionizing radiation, and its adverse effects have been extensively
documented (IARC, 2000b, 2001; UNSCEAR, 2000a, b; Ron, 2003; NRC, 2006). Exposure to
ionizing radiation has been shown to result in numerous types of cancer including several types
of leukemia as well as adverse effects that are likely to be involved in leukemogenesis including
myelotoxicity, immune suppression, and genetic damage leading to chromosomal and gene
mutations. The earliest association between radiation and cancer was seen for leukemia, and it
has been repeatedly seen in numerous population studies including those exposed through
medical, military, and environmental exposures (IARC, 2000b, 2001; UNSCEAR, 2000b; Ron,
2003; NRC, 2006).It should be noted that there are a variety of types of radiation and radioactive
materials. Most of the studies that have been conducted have investigated the effects of ionizing
radiation, which for simplicity, will be considered as one individual agent in this section.
Assessing the risks associated with radiation exposure is challenging and is influenced by the
type of radiation, the tissue dose, the proportion of the body exposed, the extent of cell killing,
and the DNA-repair capacity of the individual or tissue (Curtiset al., 1994). Host factors such as
age, sex, genetic composition, and health of the exposed individuals can also influence the risk of
radiation-induced leukemia.
All age groups are affected, but children, in particular, have been shown to be at an
elevated risk for radiation-induced leukemia as seen in the Life Span Study of the atomic bomb
survivors in Hiroshima and Nagasaki. Among the survivors who were exposed to both gamma,
and to a lesser extent, neutron radiation, the highest leukemia risks were seen in children
(Prestonet al., 1994, 2004). Significant dose-related increases were seen for ALL, AML, and
CML, with the excess risks for ALL and CML being approximately 100% higher in the exposed
males than in the females. When the leukemias were reclassified using the FAB classification
scheme, all AML subtypes were present with a predominance of myeloblastic leukemias with
and without maturation (Ml and M2) (Matsuoet al., 1988). Among the ALL cases, most cases
exhibited the L2 subtype, but a significant portion also showed the LI subtype. Latency periods
were shorter for those under 15 years of age with a leukemia peak at 5-7 years post exposure as
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compared to later peaks for those exposed at later ages (Kamada and Tanaka, 1983). The
leukemia risk also decreased more rapidly in children as compared to those in older age groups.
Overall, the risks to children were highest during the period from 1950 to 1965 and returned to
near background levels thereafter (Prestonet al., 1994).
Similarly, the use of radiation for medical purposes has been associated with increases in
leukemia. Increased risk of leukemia has been reported following the use of radiation for
diagnostic tests, for the treatment of benign diseases, and following radiotherapy for cancer
(Ron, 1998, 2003). For hematopoietic and lymphoid tissues that are diffuse, a significant portion
of the tissue must be irradiated to increase the incidence of neoplasia (Storeret al., 1982). The
leukemia risks from medical irradiation appear to have diminished in recent years due to a use of
lower and more restricted doses as well as changes in therapeutic strategy in which high doses
are applied within limited fields. High radiation doses (above 3-4 Gray) result in extensive
killing of marrow-containing progenitor cells and have been associated with a reduced risk of
developing leukemia (Boiceet al., 1987; NRC, 1990; Curtiset al., 1994).
5.2. CHEMOTHERAPEUTIC AGENTS
Following the initiation of intensive chemotherapy with genotoxic agents, increases in
therapy-related leukemias began to appear (Seiber and Adamson, 1975; Kantaijian and Keating,
1987; Levine and Bloomfield, 1992; Leoneet al., 1999). These leukemias, also known as
treatment-related or secondary leukemias, consisted primarily of AML, although a small increase
in therapy-related ALL has also been seen (Hungeret al., 1992; Andersenet al., 2001). With
increased periods of follow-up, increases in other types of solid tumors have also been observed
(Tuckeret al., 1988; Loescheret al., 1989; Boffetta and Kaldor, 1994; van Leeuwenet al., 1994;
Vega-Stromberg, 2003; Traviset al., 2005; Hodgsonet al., 2007).
Over time as new agents and therapeutic strategies have been employed, additional
agents have been recognized as inducing leukemia in humans. Indeed as seen in Table 7,
chemotherapeutic drugs comprise the largest group of agents generally recognized as human
leukemia-inducing agents. Currently, therapy-related leukemias constitute 10 to 20% of the
leukemia cases seen at major medical institutions (Deschler and Lubbert, 2006;
Pedersen-Bjergaardet al., 2007).
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The identification of specific agents involved in leukemogenesis and the interpretation of
many of the studies can be challenging due to the use of multiple therapeutic agents, varying
dosing regimens, concurrent use of radiotherapy, and variable periods of patient follow-up. Over
time, two main classes of leukemogenic therapeutic drugs have been identified—alkylating
agents and topoisomerase II inhibitors (Pedersen-Bjergaard and Philip, 1991; Pedersen-Bjergaard
and Rowley, 1994; Pedersen-Bjergaardet al., 2006). An overview of the leukemias (including
myelodysplastic syndromes) induced by these two classes of chemotherapeutic drugs will be
briefly discussed in the following sections.
5.2.1. Alkylating Agent-Related Leukemias
A large number of studies have demonstrated that patients treated with alkylating agent-
based chemotherapy are at an increased risk of MDS and AML (Levine and Bloomfield, 1992;
Pedersen-Bjergaard and Rowley, 1994; Smithet al., 1994). These risks have been seen for both
children and adults and are strongly related to the cumulative dose of the alkylating agent
(Pedersen-Bjergaard and Philip, 1987; Tuckeretal., 1987; Hungeret al., 1992;
Pedersen-Bjergaardet al., 2000; Pyattet al., 2005). The administered agents also exhibit varying
degrees of hematopoietic toxicity, immunotoxicity, and genotoxicity, which can also be affected
by the agent, dose, and route of administration (Gale, 1988; Ferguson and Pearson, 1996;
Sanderson and Shield, 1996). The incidence of treatment-related MDS and AML
(t-MDS/t-AML) in adults treated with antineoplastic drugs has been reported to range from 1%
to >20% (Felix, 1998; Leoneet al., 2001). The increases in this type of therapy-related leukemia
generally appear 1 to 2 years after treatment and may remain elevated for 8 or more years
following the completion of chemotherapy (Pedersen-Bjergaard and Philip, 1987;
Pedersen-Bjergaard and Philip, 1991; Davies, 2000; Schonfeldet al., 2006).
In adults, leukemias induced by alkylating agents exhibit characteristics that generally
allow them to be distinguished from de novo leukemias and those induced by topoisomerase II
inhibitors (Pedersen-Bjergaard and Rowley, 1994; Eastmondet al., 2005). These leukemias are
typically myeloblastic with or without maturation (FAB Ml and M2 subtypes) and are
characterized by trilineage dysplasia and clonal unbalanced chromosome aberrations, most
commonly involving loss of the entire chromosome or part of the long arms of chromosomes
5 and 7 (-7, 7q-, -5, 5q-). These t-AML have a modal latency of 4-7 years, and the onset of
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the actual leukemia is often preceded by myelodysplasia. It should be noted that AML induced
by ionizing radiation tends to exhibit similar features (MDS, clonal unbalanced chromosomal
aberrations, etc.) although the range of the FAB subtypes induced by radiation tends to be
broader (Matsuoet al., 1988; Philip and Pedersen-Bjergaard, 1988; Gundestrupet al., 2000).
Using structure-activity relationships as well as other predictive approaches with in vivo
rodent and Drosophila data, Vogelet al. (1998) were able to identify three major categories of
DNA-reactive chemical and therapeutic agents. As described by the authors, Category 1
consisted of mono-functional alkylating agents such as ethylene oxide and methyl methane
sulfonate, which primarily react at the N7 and N3 moieties of purines in DNA. Efficient DNA
repair was the major protective mechanism against the relatively weak genotoxic effects of these
agents, which might not be detectable in repair-competent cells. High doses were generally
needed for the induction of tumors in rodents. A strong target site specificity for the adverse
effects was seen, and this appeared to be related to DNA repair capacity. Category 2 agents such
as procarbazine and A'-nitroso-A'-ethylurea (ENU) induce both O-alkyl adducts and A-alkyl
adducts in DNA. In general, the induced O-alkyl adducts appeared to be slowly repaired, or not
repaired, which made these agents potent carcinogens and germ cell mutagens. The inefficient
repair of the O-alkyl-pyrimidines, in particular, was responsible for their potent mutagenic
activity. Category 3 agents such as melphalan and busulfan induced structural aberrations
through their ability to cross-link DNA, and this was the major factor contributing to their high
genotoxic potency, which appeared to be related to the number of DNA crosslinks per target
dose unit that were induced. The genotoxic effects for the Category 3 agents occurred at, or
near, toxic levels. For all three categories of genotoxic agents, strong correlations were observed
between their carcinogenic potency, acute toxicity, and germ-cell specificity.
5.2.2. Topoisomerase II Inhibitor-Related Leukemias
In the late 1980s, a new type of therapy-related leukemia was recognized that exhibited
unusual features that differed from those previously seen following treatment with alkylating
agents and radiation (Puiet al., 1989; Pui and Relling, 2000). The affected patients had been
treated with etoposide or teniposide, two of a newly developed epipodophyllotoxin class of
chemotherapeutic agents (Pedersen-Bjergaard and Philip, 1991). In the ensuing years, these
epipodophyllotoxins have become widely used, especially for treating childhood cancers, and a
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large number of studies have been published establishing an association between treatment with
these drugs and the subsequent development of leukemia (Hauptet al., 1993; Smithet al., 1994;
Pedersen-Bjergaardet al., 1995; Pui and Relling, 2000; Leoneet al., 2001; Hijiyaet al., 2009).
The leukemia risk following epipodophyllotoxin therapy was reported to be very high in
early studies, with cumulative incidences approaching 19% in some treatment groups (Puiet al.,
1989). Interestingly, in some cases, the risk of a secondary cancer appeared to be more closely
related to the treatment regimen than to total dose (Puiet al., 1991; Pui and Relling, 2000).
Patients receiving epipodophyllotoxins on a weekly or twice-weekly basis had much higher
cumulative risks (12.4%) than those receiving the drugs on a biweekly schedule (1.6%). Similar
results have been seen in more recent studies (Smithet al., 1999) although others have seen a
correlation between cumulative dose and epipodophyllotoxin-induced t-AML (Negliaet al.,
2001; Le Deleyet al., 2003). With implementation of newer treatment protocols, the risk of
t-AML has been reduced substantially and is now within the range of that seen with alkylating
chemotherapeutic agents (Smithet al., 1993; Pui and Relling, 2000). There is also evidence that
the combined treatment of topoisomerase II inhibitors with alkylating agents (or cisplatin)
confers a greater risk of t-AML than seen with either type of chemotherapeutic agent alone
(Sandovalet al., 1993; Smithet al., 1994; Blatt, 1995). In most reported cases, the incidence of
t-AML induced by these drugs is estimated to range from 2 to 12% (Felix, 1998; Leoneet al.,
2001).
The epipodophyllotoxins exhibit moderate myelosuppression, identifiable chromosomal
damage, and their leukemogenic effects by inhibiting topoisomerase II through a process that
involves stabilization of the DNA-enzyme complex (Smithet al., 1994; Ferguson and Pearson,
1996). Topoisomerase II is a nuclear enzyme involved in a wide variety of cellular functions,
including DNA replication, transcription, and chromosome segregation (Anderson and Berger,
1994; Nitiss, 2009). Leukemias induced following treatment with epipodophyllotoxin-type
topoisomerase inhibitors appear from 10 months to 8 years following the initiation of
chemotherapy, with a median latency of 2 to 3 years (Smithet al., 1994; Leoneet al., 2001). The
induced AMLs are primarily of the monocytic or myelomonocytic subtypes (M4 and M5) and
are rarely preceded by a myelodysplastic phase, a pattern that differs significantly from
alkylating agent or radiation-induced leukemias (Pedersen-Bj ergaard and Rowley, 1994; Smithet
al., 1994; Leoneet al., 2001; Pedersen-Bjergaardet al., 2006).
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Infrequently, ALL has been reported in patients following treatment with both alkylating
agents and topoisomerase Il-inhibiting drugs (Hungeret al., 1992; Andersenet al., 2001; Hijiya et
al., 2009). Although t-ALLs occur infrequently, they seem to be more common in children
under the age of 15 who have previously been treated with a topoisomerase II inhibitor
(Andersenet al., 2001).
One of the unique features of t-AML, and to a lesser extent t-ALL, induced by the
epipodophyllotoxin-type of topoisomerase II inhibitors, is the presence of clonal-balanced
translocations involving the MLL gene (also known as ALL-1, HRX, and HTRX-1) located on
the long arm of chromosome 11 (1 lq23) in the leukemic cells. Cytogenetic studies of patients
with leukemias induced by these agents have shown that in over 50% of the cases, the leukemic
clone involved a balanced translocation affecting the 1 lq23 region and another chromosomal
partner, usually t(6; 11), t(9; 11), and t(l 1; 19) (Pedersen-Bjergaard and Rowley, 1994; Smithet al.,
1994; Canaaniet al., 1995). In children previously treated with topoisomerase inhibitors, up to
90% of the secondary leukemias have an 1 lq23 alteration (Canaaniet al., 1995). As indicated
previously, to date, 87 rearrangements involving the MLL gene have been identified, and 51 of
the translocation partner genes have been characterized at the molecular level (Meyeret al.,
2006). The four most common MLL translocation partner genes (AF4, AF9, ENL, and AF10)
encode nuclear proteins that are part of a protein network involved in histone H3K79
methylation (Meyeret al., 2006) indicating an important role for this pathway in
epipodophyllotoxin leukemogenesis.
Numerous lines of evidence indicate that topoisomerase II as well as DNA-repair
enzymes such as those involved in non-homologous end joining play an important role in the
formation of the 1 lq23 translocations. These have been summarized in series of reviews
(Greaves and Wiemels, 2003; Apian, 2006; Felixet al., 2006; Zhang and Rowley, 2006). The
presence of topoisomerase II recognition sites has been found in proximity to the translocation
breakpoints as have recombinase recognition sites, Alu sequences, DNase hypersensitive sites,
and scaffold attachment regions and suggest that multiple types of damage and repair probably
contribute to the generation of the observed translocations (Pui and Relling, 2000; Felixet al.,
2006; Zhang and Rowley, 2006). Interestingly, in a recent report, Le et al., (2009) reported that
the translocation breakpoints within the MLL gene occurred in a highly specific fashion at the
base of a secondary DNA structure formed from a palindrome. A stringent topoisomerase II
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consensus binding site was located at the apex of the secondary DNA structure. The authors
proposed a model in which topoisomerase II facilitates the formation of a secondary structure
that results in site-specific DNA strand breakage that is efficiently processed into translocations
(Leet al., 2009). This processing most likely occurs through a mechanism involving
nonhomologous end joining (Greaves and Wiemels, 2003; Zhang and Rowley, 2006). It should
also be noted that the MLL gene has been shown to be prone to breakage during apoptosis, and it
has been proposed that the observed translocations occur in hematopoietic cells rescued at an
early, reversible stage during the apoptotic process (Stanullaet al., 1997; Bettiet al., 2005;
Vaughanet al., 2005; Baseckeet al., 2006). A role for apoptosis has also been proposed in the
formation of other leukemia-related translocations (Eguchi-Ishimaeet al., 2001).
5.2.3. Other Likely Leukemia-Inducing Therapeutic Agents
In recent years, evidence has accumulated that other inhibitors of topoisomerase II, such
as the anthracycline, anthracenedione, and bisdioxopiperazine derivatives, can also induce
secondary leukemias (Xueet al., 1992; Zhanget al., 1993; Blatt, 1995; Andersenet al., 1998;
Le Deleyet al., 2003; Mistryet al., 2005; Mayset al., 2010). The leukemias induced by these
agents are similar to the epipodophyllotoxins in that they have short latency periods and are
infrequently preceded by myelodysplasia. However, they typically exhibit different types of
clonal-balanced rearrangements (e.g., t(8;21), t(l 5; 17), and inv(16)) and different FAB subtypes
(M2 and M3).
Although azathioprine, 6-thioguanine, and 6-mercaptopurine are primarily associated
with immunosuppression and the induction of NHL, a number of studies have suggested that
patients treated with these 6-thioguanosine monophosphate-producing drugs are at an increased
risk of developing ANLL (Boet al., 1999; Karran, 2006; Yensonet al., 2008). It has been
suggested that the risks are higher in patients with low thiopurine »Y-methyl transferase activity
and may involve aberrant mismatch repair and microsatellite instability (Boet al., 1999; Karran,
2006). Interestingly, the leukemias of many of these patients also show loss of chromosome 7 or
part of chromosomes 5 or 7 (5q- or 7q-) (Yensonet al., 2008).
A summary of the types of leukemia and related lymphoid neoplasms as well as key
characteristics of the leukemias induced by different types of leukemia-inducing agents is
presented in Table 9. Information on leukemias induced by the bisdioxopiperazine class of
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1 topoisomerase II inhibitors has also been added to facilitate comparisons with benzene. There is
2 recent evidence to suggest that one mechanism by which benzene induces leukemia is through
3 inhibition of topoisomerase II by a mechanism that may be similar to that of the
4 bisdioxopiperazine class of topoisomerase II inhibitors (Mondrala and Eastmond, 2009).
5
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6. MECHANISMS INVOLVED IN t-AML
For more than 20 years, Pedersen-Bjergaard and colleagues have collected information
on patients with t-AML and t-MDS who have been treated at their clinic in Copenhagen,
Denmark. Based on the genetic alterations seen in this cohort of 140 patients as well as
information in the literature, they have identified eight separate pathways that appear to lead
either directly to t-AML or lead to t-MDS and then to t-AML. These pathways are illustrated in
Figure 3 (from [Pedersen-Bjergaardet al., 2006]). The pathways have been classified into three
groups largely based upon the therapeutic agent that was likely responsible for the leukemia.
Each of the pathways is described below based on descriptions extracted from their 2006 article
(i.e., Pedersen-Bjergaardet al., 2006).
Pathway I in the figure was characterized by patients who developed t-MDS prior to
t-AML and exhibited either loss of chromosome 7 or part of the long arm of that chromosome
(7q-). These patients also did not exhibit the recurrent balanced translocations that are
associated with AML. Most of these patients (35/39) had been treated with alkylating agents,
and most (35/39) presented with t-MDS prior to t-AML. Methylation of the pl5 promoter,
considered a late event in leukemogenesis, was seen in 84% of the patients. In addition to the
chromosome 7 changes, the leukemias of a significant portion (15/39 or 38%) of these patients
had point mutations in the AML1 (also known as RUNX1) gene. A number of these patients
also had mutations in either the TP53 tumor suppressor gene or an activating mutation in the
RAS oncogene.
Pathway II predominated in patients that exhibited loss of all (-5) or part of the long arm
of chromosome 5 (5q-). Approximately half of the patients in this group also had -7 or 7q-
alterations. As with Pathway I, onset of this disease is closely related to the use of alkylating
agent chemotherapy (27/34) and an initial presentation as t-MDS (26/34). Seventy-seven percent
of these patients exhibited mutations in TP53. The patients also often present with a complex
karyotype, loss of part of the short arm of chromosome 17 (17p-), or showed an amplification or
duplication of chromosome bands 1 lq23 or 21q22. Methylation of the pi 5 promoter occurred in
80-90%) of the patients of this group.
Pathway III was characterized by balanced translocations involving the 1 lq23
chromosome band and one of many partner chromosomes. These translocations frequently
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occurred in patients who had been previously treated with topoisomerase II inhibitors and
exhibited AML of the FAB subtypes M4 or M5. Three of the 11 patients in this group had a
RAS mutation, and another 3 had a BRAF mutation. Methylation of the pi 5 promoter was seen
in 50% of the patients.
Pathway IV occurred in patients with balanced translocations involving chromosome
bands 21q22 or 16q22 leading to chimeric rearrangements involving the core binding factor
genes AML1 or CBFB. These chromosomal changes are generally associated with previous
treatment with topoisomerase II inhibitors, most commonly of the anthracycline class. While
patients in this group with a t(3;21)(q26;q22) often present as t-MDS, most of the others present
directly with t-AML. Chromosome 7 alterations were also seen in five of nine patients with
21q22 translocations. Point mutations in c-Kit and PTPN11 were seen in a few patients.
Methylation of the pi 5 promoter was seen in 83% of the patients.
Pathway V occurred in only two patients and is characterized by a translocation between
chromosomes 15 and 17 involving the PML and RARA genes. Therapy-related promyelocytic
leukemia (M3) that exhibits the characteristic t(15; 17) has been reported to occur in patients
treated with doxorubicin or mitoxanthrone. One of the patients in this group also had a mutation
due to FLT3 internal tandem duplication.
Pathway VI is an uncommon pathway in which t-AML patients exhibit balanced
translocations involving the NU98 gene at chromosome band 1 lpl 5. None of the 140 patients in
the Copenhagen series exhibited this pattern.
Pathway VII exhibits a normal karyotype, and most often presents directly as t-AML.
Approximately 17% of the patients in the Copenhagen series fell within this group and have not
been consistently associated with any previous type of chemotherapy. The mutations seen are
also commonly seen in de novo leukemias suggesting that these may represent sporadic cases of
de novo leukemia occurring in these patients. Methylation of the pi 5 promoter was only seen in
50% of these patients.
Pathway VIII is composed of patients that exhibit unique or unusual chromosome
alterations and represents 14% of the Copenhagen cohort. These cases do not show an
association to any specific type of previous therapy and may also represent cases of de novo
leukemia. Methylation of the pi 5 promoter was also uncommon occurring in 40% of the cases.
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1 Consistent with the description presented above, patients with t-AML with leukemic cells
2 exhibiting loss of all or part of chromosomes 5 or 7, frequently present initially with t-MDS and
3 have often been previously treated with alkylating agent chemotherapeutic drugs. In contrast,
4 t-AML exhibiting certain specific reciprocal translocations such as t(l lq23) and t(21q22) occur
5 in patients that were previously treated with a topoisomerase II-containing chemotherapeutic
6 regimen and develop without a preceding MDS.
7
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7. FACTORS CONFERRING AN INCREASED RISK OF INDUCED LEUKEMIA
7.1. MYELOSUPPRESSION AND IMMUNOTOXICITY
Myelosuppression and immunotoxicity frequently accompany exposure to leukemia-
inducing agents, particularly those such as the chemotherapeutic drugs, ionizing radiation, and
benzene, for which leukemogenicity has been clearly established (Ferguson and Pearson, 1996;
Eastmond, 1997). The number of individuals affected and the magnitude of toxicity are
influenced by the agent and dose-related factors such as total dose, dose per treatment, schedule,
and route of administration as well as individual host factors (genetic susceptibility, prior
therapy, health status, etc.) (Gale, 1988). A brief overview of the myelosuppressive effects of
cancer therapeutic drugs has been written by Gale (1988) and is the basis for the following
description. The severity of myelotoxicity induced by antineoplastic drugs varies considerably
by chemical class. For drugs associated with t-AML, moderate-to-severe effects are generally
seen. The epipodophyllotoxins, cisplatin, and procarbazine typically produce more moderate
toxicity whereas severe effects are more common for the alkylating agents, the anthracyclines,
and the nitrosoureas.
The period between dosing and the onset or appearance of the myelosuppression is also
related to the class of agent. For some agents such as ionizing radiation, the onset of
myelotoxicity occurs within 0 to 48 hours after exposure. For others, longer periods are
required. The onset of myelosuppression by the alkylating agents and anthracyclines occurs 1 to
3 weeks following exposure and is believed to be due to the effect of these agents on immature
hematopoietic cells that becomes more evident as the more mature blood cells die and require
replacement. Myelosuppression induced by the nitrosoureas and mitomycin C is less frequent
and occurs 4 to 8 weeks after treatment. This delayed effect is believed to be due to a relatively
selective effect on immature stem cells. However, the onset of this delayed effect is dose-
dependent. A two- to three-fold increase in dose reduces the onset of myelotoxicity to 1 week.
For some drugs such as busulfan, the manifestation of the myelotoxic effects is considered to be
latent and may only be manifested under stress-related conditions.
In most cases, the induced myelotoxicity is transient with the blood cell counts returning
to normal following the cessation of treatment or exposure (Hendry and Feng-Tong, 1995;
Ironset al., 2005). However, in some cases, the induced myelosuppression can be more
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persistent and progress to pancytopenia or infrequently to aplastic anemia, a condition that
confers a much greater risk of developing leukemia (-10%) (Aksoyet al., 1984; Jandl, 1987;
Oharaet al., 1997; Imashukuet al., 2003). Increased risks have also been seen for those who have
previously exhibited less severe forms of bone marrow toxicity. Studies of benzene-exposed
workers have shown that the leukemia mortality rate was much higher for workers who had
previously been diagnosed with bone marrow poisoning (700 per 106 person-years) as compared
to those exposed to, but not poisoned by, benzene (14 per 106 person-years), and particularly as
compared to the general population (2 per 106 person-years) (Yin and Li, 1994). In one report,
36% of the benzene leukemia cases had a history of benzene poisoning with leukopenia or
pancytopenia (Yinet al., 1994). However, this also indicates that for most cases, clinically
detectable myelotoxicity may not be observed. It should also be noted that at lower exposure
levels, the decreases in cell counts occurring in exposed groups may fall within what is
considered the normal clinical range (Quet al., 2002; Lanet al., 2004). This highlights one of the
challenges in using myelotoxicity as a biomarker, as the normal range varies considerably in
"3
adults. For example, the mean white blood cell count in adults is 7,200 x 10 !\iL with a 95%
range from 3,900 to 10,900 x 103/|iL (Jandl, 1996).
7.2. GENETIC POLYMORPHISMS
Inherited polymorphisms in genes involved in xenobiotic metabolism and other cellular
processes have been associated with increased risks of myelotoxicity or leukemia in numerous
studies of patients or workers exposed to leukemogenic agents. In some instances, similar
associations have been seen in follow-up studies by other investigators. However, in a
significant number of cases, the results have either not been repeated or have not been
reproducible. Consequently, it is difficult to make firm conclusions about many of the reported
polymorphisms. Several recent reviews on polymorphisms and leukemia have been published
that the reader may want to refer to for further details (Cheok and Evans, 2006; Cheoket al.,
2006; Sinnettet al., 2006; Seedhouse and Russell, 2007). The following is a brief overview of
some of the genetic polymorphisms involved in DNA metabolism, repair, and xenobiotic
metabolism that have been repeatedly associated with altered risks of developing leukemia,
particularly induced leukemias.
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Since most leukemogens are genotoxic and exert their effects by damaging DNA, the
DNA repair capacity of the bone marrow is likely to have a significant influence on the risk of
t-AML. Indeed, individuals with congenital deficiencies in enzymes that are involved in DNA
repair such as ataxia telangiectasia, Bloom syndrome, and Fanconi anemia are at significantly
higher risk for developing leukemia and other lymphohematopoietic cancers (Segel and
Lichtman, 2004). Individuals with these and other uncommon genetic syndromes such as
neurofibromatosis 1 are also at an increased risk of t-AML following treatment with radiation,
alkylating agents, and/or topoisomerase II inhibitors (Mariset al., 1997; Seedhouse and Russell,
2007).
Genetic polymorphisms in DNA repair genes that occur more frequently in the
population can also confer an increased risk of t-AML. Defective mismatch repair is often
manifested by microsatellite instability in the cancer cells. Microsatellite instability is frequently
seen in leukemias, particularly in t-AML, where it has been reported to occur in -50% of the
cases (Karranet al., 2003; Seedhouse and Russell, 2007). In contrast, less than 5% of de novo
leukemias exhibit microsatellite instability. While the basis for this instability is still unknown,
factors that may contribute are deficiencies in DNA-mismatch repair enzymes. In a fairly recent
report, the hMSH2 mismatch repair variant was shown to be significantly overrepresented in
t-AML patients that had previously been treated with 06-guanine-forming alkylating agents
including cyclophosphamide and procarbazine, as compared with controls (Worrillowet al.,
2003). Similarly, polymorphisms in genes involved in DNA repair (e.g., WRN, TP53, hOGGl,
XRCC1, ERCC3, and BRCA2) have been reported by a number of investigators to be associated
with a decrease in white blood cell counts or an increase in chromosomal damage in benzene-
exposed workers or workers previously poisoned by benzene (Shenet al., 2006; Kimet al., 2008;
Wuet al., 2008; Hosgoodet al., 2009; Sunet al., 2009).
Polymorphisms affecting DNA metabolism have also been reported to confer an
increased risk of t-AML. Thiopurine methyltransferase (TMPT) catalyzes the »Y-methyl ation of
thiopurine medications such as 6-mercaptopurine and 6-thioguanine, which are commonly used
as chemotherapeutic agents. As summarized from Cheok and Evans (2006), the thiopurine
methyltransferase pathway is the primary mechanism for inactivation of thiopurines in
hematopoietic tissues. The link between thiopurine methyltransferase polymorphisms and
mercaptopurine toxicity has been extensively investigated, and studies have shown a strong
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relationship between thiopurine methyltransferase deficiency polymorphisms and hematopoietic
toxicity. Three variant alleles are responsible for >95% of the cases with low or intermediate
thiopurine methyltransferase activity. Patients homozygous or heterozygous for the low activity
alleles are inefficient at detoxifying the mercaptopurines and accumulate high concentrations in
their hematopoietic tissues. If their administered doses are not modified, they are at high risk for
severe hematopoietic toxicity. Inherited thiopurine methyltransferase deficiency has also been
associated with a higher risk of t-AML, particularly in ALL patients treated with topoisomerase
II inhibitors (Thomsenet al., 1999; Gadneret al., 2006). It has been postulated that the increased
risk may be due to an interference of 6-thioguanine or methylated 6-mercaptopurine with DNA
repair after DNA damage has been induced by other chemotherapeutic agents.
The influence of polymorphisms in other xenobiotic metabolizing genes on the incidence
of leukemia has been the subject of many investigations (Cheoket al., 2006; Leoneet al., 2007;
Seedhouse and Russell, 2007; Guillem and Tormo, 2008; Leoneet al., 2010). In many cases,
there was no difference between the frequencies seen in t-AML patients as compared to de novo
leukemia patients or a control cohort. A number of studies have indicated that individuals with
genes coding for nonfunctional or less active copies of various glutathione-»Y-transferases,
CYP3A4, and NADPH-quinone-oxidoreductase 1 (NQOl) have an increased risk for developing
t-AML following chemotherapy. However, these results have not consistently been seen. The
relationship between NQOl and leukemia is presented below as an example.
Polymorphisms in NQOl, an enzyme involved with the reduction of quinones and
protection against oxidative stress, have been repeatedly associated with the development of
leukemia. Studies have reported that an inactivating polymorphism in NQOl (the C609T slow
variant) was overrepresented in patients with t-AML (Larsonet al., 1999), in those with de novo
AML (particularly those with translocations or an inv (16) clonal aberration [Smithet al., 2001]),
and in infant leukemias with a 1 lq23 karyotype, and infants and children with the t(4; 11) form of
ALL (Wiemelset al., 1999; Smithet al., 2002). While these initial studies indicated a consistent
association with a number of different leukemia types, more recent studies have been less
consistent with many not showing an association (Blancoet al., 2002; Sirmaet al., 2004;
Eguchi-Ishimaeet al., 2005; Maliket al., 2006).
Genetic polymorphisms affecting NQOl have also been associated with increased
myelotoxicity and may confer an increased risk of leukemia. For example, benzene-exposed
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individuals who were rapid CYP2E1 metabolizers and had the C609T slow variant for NQOl
had a 7.6-fold increased risk of benzene poisoning as compared to exposed individuals with the
slow metabolizer phenotype who had one or two of the wild type NQOl alleles (Rothmanet al.,
1997). In another study by this research group, different NQOl polymorphisms, as well as a
polymorphism in myeloperoxidase, an enzyme implicated in the bioactivation of benzene's
quinone metabolites in the bone marrow, were associated with lower blood cell counts in
benzene-exposed workers (Lanet al., 2004). A similar association between NQOl and
chromosomal damage in the peripheral blood lymphocytes of benzene-exposed was also recently
reported by another research group (Kimet al., 2008).
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8. EXAMPLES OF SPECIFIC LEUKEMIA-INDUCING CHEMICALS
The information on the mechanisms of action of the various leukemia-inducing agents
presented in the following section has been extracted and summarized from the respective IARC
monographs.
8.1. MELPHALAN
A modified version of the section below will be published in a forthcoming issue of the
IARC monographs.
The antineoplastic drug melphalan is a direct-acting, bifunctional alkylating agent that
binds to cellular macromolecules including DNA, RNA, and proteins (Osborneet al., 1995). As
a phenylalanine derivative of nitrogen mustard, it is capable of producing a variety of DNA
adducts including monoadducts at the N7 of guanine and the N3 of adenine as well as interstrand
crosslinks - premutagenic lesions that are believed to play a critical role in its toxic and
carcinogenic effects (Povirk and Shuker, 1994; Lawley and Phillips, 1996; GlaxoSmithKline,
2007). In the classification scheme of Vogel et al., 1998, melphalan is a Category 3 agent that
would be expected to be a potent mutagen and carcinogen.
Melphalan has been tested for genotoxicity in an assortment of short-term tests, with
positive results seen in a wide variety of assays both in vitro and in vivo(IARC, 1987a, b).
Increased frequencies of chromosomal aberrations and sister chromatid exchanges (SCEs)
occurring in the peripheral blood lymphocytes have also been reported in multiple studies of
patients treated therapeutically with melphalan (IARC, 1987a; Raposa and Varkonyi, 1987;
Mamuriset al., 1989, 1990; Poppet al., 1992; Amielet al., 2004). Patients treated with this
anticancer agent have also exhibited hematotoxicity and immunosuppression (Goldfranket al.,
2002; GlaxoSmithKline, 2007).
As indicated in the most recent IARC evaluation, patients treated with melphalan are at a
significantly elevated risk of developing ANLL (Grosseet al., 2009) (see Table 7). Leukemias
that have developed in patients previously treated with melphalan (often in combination with
other agents) have shown the alterations involving chromosomes 5 and 7 that, as described
above, are characteristic of t-AML induced by alkylating agents (Rodjeret al., 1990). While
there is some evidence that melphalan may directly induce damage targeting chromosomes 5 or 7
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(cf. Mamuriset al. [1989, 1990] and Amielet al. [2004]), this drug has also been reported to
induce nonspecific chromosomal alterations in a variety of experimental models and in the
lymphocytes of treated patients as indicated earlier. The detection of elevated levels of
chromosome aberrations in the peripheral blood lymphocytes of the treated patients is of
particular note, as multiple prospective studies have now shown that individuals with increased
levels of chromosome aberrations or micronuclei in these cells are at increased risk of
developing cancer later in life (Hagmaret al., 1998; Liouet al., 1999; Smerhovskyet al., 2001;
Hagmaret al., 2004; Boffettaet al., 2007).
8.2. ETHYLENE OXIDE (largely summarized from IARC, 2008b)
Ethylene oxide is a direct-acting alkylating agent that has been shown to bind to DNA,
RNA, and protein. The major DNA adduct recovered in vivo is N7- (hydroxyethyl) guanine, an
adduct that in not considered to be particularly mutagenic. Additional adducts such as
3-(2-hydroxyethyl)-adenine and 06-(2-hydroxyethyl)guanine, which would be expected to be
more mutagenic, are either not detected or are detected at very low levels (Walker et al., 1992).
Ethylene oxide is readily metabolized to non-DNA reactive products by glutathione-
s-transferases and epoxide hydrolases, and this is likely to reduce the concentrations of ethylene
oxide that are able to reach the DNA. In the classification scheme of Vogelet al., 1998, ethylene
oxide is a Category 1 agent that would be expected to be a relatively weak mutagen and
carcinogen in vivo as compared to other, primarily antineoplastic, alkylating agents.
Ethylene oxide has been shown to be genotoxic and mutagenic in numerous assays in
both somatic and germ cells, and in both prokaryotic and eukaryotic organisms (IARC, 1994,
2008b). It is highly active in in vitro systems, with lesser activity being seen in vivo. Numerous
studies have shown that ethylene oxide can induce point mutations in both reporter genes and
cancer genes of multiple tissues in mice and rats. Based on these studies, however, ethylene
oxide was considered to be a relatively weak point mutagen in vivo. Ethylene oxide was shown
to induce chromosomal damage in rodents, but observable damage occurred only at high
concentrations indicating that it is also a relatively weak clastogen in experimental animals.
Somewhat surprisingly, increased frequencies of chromosomal aberrations have been seen in the
peripheral blood lymphocytes of ethylene oxide-exposed workers in 18 of 24 studies that were
evaluated (IARC, 2008b). As indicated above, individuals with elevated frequencies of
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chromosomal aberrations in their peripheral blood are at an elevated risk of developing cancer.
Ethylene oxide induced lymphohematopoietic cancers in female mice (lymphomas) and male
and female rats (mononuclear cell leukemia) in chronic bioassays. In contrast to most other
leukemia-inducing agents, exposure to ethylene oxide has not been associated with myelotoxicity
in humans.
In two fairly recent studies, an elevated frequency of mutations or a change in mutational
spectra was seen in the tumors of ethylene oxide-treated mice (Houleet al., 2006; Honget al.,
2007). High frequencies of K-Ras mutations were detected in the lung, Harderian gland, and
uterine tumors of the ethylene oxide-treated animals. A minor increase in mutation frequency
and a major change in the mutational spectrum of Tp53 mutations were also seen in mammary
gland tumors of ethylene-oxide treated mice (Houleet al., 2006). The high frequencies of
mutations present in these genes, particularly mutations in the critical codons of K-Ras and
inactivation of Tp53, indicate that mutations are induced in the tumors of ethylene oxide-treated
mice, and that the changes likely play an important role in ethylene oxide-induced tumorigenesis
in these tissues.
There is little known about the mechanisms underlying ethylene oxide-induced tumors in
humans. However, activating mutations in the RAS family of oncogenes and inactivation of
TP53 have been shown to play critical roles in the development of both spontaneous and
chemically induced cancers (Pedersen-Bjergaardet al., 2006; Zarbl, 2006). Of note, activating
mutations in RAS genes have been shown to occur in up to 30% of AML cases (Byrne and
Marshall, 1998). In most cases, it is N-/^AY that is activated although activation of K-RAS is
occasionally seen (Byrne and Marshall, 1998; Bowenet al., 2005). The mutations typically occur
in codons 12, 13, and 61, sites that are critical for the normal regulation of RAS activity. The
activating mutations lead to the generation of constitutively activated RAS proteins that cannot be
switched off and inappropriately generate proliferative signals within the cell (Byrne and
Marshall, 1998). While RAS mutations occur frequently in de novo AML, they are generally
less commonly seen in t-MDS/t-AML. As shown in Table 6, they were only seen in 14 of the
140 patients in the Copenhagen cohort (Christiansenet al., 2005; Pedersen-Bjergaardet al., 2008).
Some patients that lack RAS mutations still exhibit an overexpression of RAS genes, and this has
been considered as further evidence for the involvement of dysregulated RAS signaling in
leukemogenesis (Byrne and Marshall, 1998). Interestingly, an elevated expression of the N-/^AY
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oncogene (as well as the TP53 tumor suppressor gene) was reported in the lymphocytes of two
small groups of ethylene oxide-exposed hospital nurses (Emberet al., 1998a, b).
Mutations in the TP53 tumor suppressor gene have also been detected in a subset of
t-MDS/t-AML patients. For example, 34 of the 140 patients in the Copenhagen cohort exhibited
TP53 mutations (Pedersen-Bjergaardet al., 2008). These were typically seen in patients whose
leukemia cells exhibited a loss of all or part of chromosomes 5 and 7.
In its recent evaluation (Baanet al., 2009; IARC, 2009), the IARC working group
indicated that "there is limited evidence in humans for a causal association of ethylene oxide with
lymphatic and haematopoietic cancers (specifically lymphoid tumors, i.e., non-Hodgkin
lymphoma, multiple myeloma, and chronic lymphocytic lymphoma)...." It should be noted that
ANLL was not one of the lymphohematopoietic cancers that was considered by the IARC
working group to be associated with ethylene-oxide exposure. As a result, the information on
t-AML presented above, while valid for other types of alkylating agents, may not be relevant in
this case. As seen in Table 7, the three lymphohematopoietic cancers mentioned by IARC have
generally not been associated with other alkylating agents with the exception of butadiene, which
has been associated with CLL and NHL (described below). It should also be noted that the three
types of neoplasm listed by IARC originate in mature B lymphoid cells, which is also somewhat
unusual for alkylating agent-related cancers.
8.3. 1,3-BUTADIENE (summarized largely from IARC, 1999, 2008a)
Butadiene is a widely used industrial chemical that has been shown to induce cancer in
mice, rats, and humans. Butadiene is metabolized to a number of epoxide metabolites
(stereoisomers of epoxybutene, epoxybutanediol, and diepoxybutane) that can react directly with
DNA. The most common DNA adduct detected in mice and rats is the A'7-guanine adduct
(A'7-trihydroxybutyl guanine), which is derived from either epoxybutanediol or diepoxybutane.
Other adducts at base-pairing sites that can be formed from the epoxide metabolites of butadiene
include adducts at the A'3-cytosine, M-adenine, A'6-adenine, M-guanine, and A'2-guanine.
Crosslinks between A'7-guanines have been detected in the liver and lungs of butadiene-treated
mice. The butadiene epoxide metabolites can also be metabolized to non-DNA reactive products
by glutathione-»Y-transferases and epoxide hydrolases. In the classification scheme in Vogelet
al., 1998, butadiene through its diepoxybutane metabolite was considered a Category 3 agent,
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which would be expected to be a potent mutagen and carcinogen. However, it was suggested by
Vogel et al. (1998) that because the DNA crosslinks formed by diepoxybutane are primarily
intrastrand crosslinks that are more readily repaired, diepoxybutane is a much weaker mutagen
and carcinogen than other Category 3 agents. Metabolic factors are also likely to contribute to
butadiene's reduced potency in rats (and probably humans). However, it should be noted that
butadiene is readily bioactivated in mice and is a potent carcinogen in that species.
Butadiene and its epoxide metabolites have been shown to be genotoxic and mutagenic in
most experimental systems both in vitro (with metabolic activation for butadiene) and in vivo.
Butadiene exhibited clastogenic effects in mice inducing chromosomal aberrations, micronuclei,
and SCEs. Similar effects were not seen in rats, and this is believed to be due to metabolic
differences between the two species. Butadiene has also been shown to induce mutations with
bioactivation in mammalian cells and in vivo in mice. It should be noted that considerably fewer
studies of the genotoxicity of butadiene have been conducted in rats as compared to mice. The
genotoxicity of the epoxide metabolites has also been extensively studied. Not surprisingly
given its bifunctional nature, the diepoxybutane is the most potent of the three metabolites. For
example, when monoepoxybutene, diepoxybutane, and 3,4-epoxy-l,2-butanediol were tested for
mutagenicity at HPRT and TK loci in the TK6 human lymphoblastoid cells (Cochrane and
Skopek, 1993; Cochrane and Skopek, 1994), all three epoxides were mutagenic, but the
mutagenicity of the diepoxybutane was much greater than that seen for the other two epoxides.
However, as noted by IARC (2008a), while genotoxicity studies have indicated that
diepoxybutane is the most genotoxic of the epoxides formed from butadiene, the relative
contribution of the various epoxide metabolites to the mutagenicity and carcinogenicity of
butadiene is not known as the monoepoxybutene metabolite is likely to be formed in greater
quantities.
Using either conventional techniques or new molecular cytogenetic techniques such as
fluorescence in situ hybridization with DNA probes, increased frequencies of chromosomal
aberrations have not generally been seen in the peripheral blood lymphocytes of butadiene-
exposed workers. Exposure to butadiene has also not been associated with myelotoxicity in
exposed humans.
Mutations in the cancer-related K-Ras, H-Ras, Tp53,pl6lpl5, and b-catenin genes have
been detected in tumors of mice exposed to butadiene. K-Ras mutations, frequently a G-to-C
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transversion at codon 13, have been seen in hemangiosarcomas, lymphomas, and cancers of the
lung, forestomach, and mammary tumors of butadiene-treated mice. Mutations in the Tp53
tumor-suppressor gene have been detected in mouse lymphomas, brain tumors, and mammary
gland tumors. Similarly, mutations in thep!5 and pi 6 tumor suppressor genes were seen in
induced lymphomas, and mutations in b-catenin were seen in the mammary gland tumors. The
prevalence of mutations in these cancer-related genes provides strong evidence for a mutagenic
mechanism in butadiene carcinogenesis. As indicated above, mutations in the RAS and TP 5 3
genes have been seen in de novo leukemias and t-AMLs seen in humans.
In its 2008 evaluation (IARC, 2008a), IARC concluded
Overall, the epidemiological studies provide evidence that exposure to butadiene
causes cancer in humans. ... This conclusion is primarily based on the evidence
for a significant exposure-response relationship between exposure to butadiene
and mortality from leukaemia in the University of Alabama in Birmingham study,
which appears to be independent of other potentially confounding exposures. It is
also supported by elevated relative risks for non-Hodgkin lymphoma in other
studies, particularly in the butadiene monomer production industry. The Working
Group was unable to determine the strength of the evidence for particular
histological subtypes of lymphatic and haematopoietic neoplasms because of the
changes in coding and diagnostic practices for these neoplasms that have occurred
during the course of the epidemiological investigations. However, the Working
Group considered that there was compelling evidence that exposure to butadiene
is associated with an increased risk for leukaemias.
The most recent IARC evaluation (Baanet al., 2009; IARC, 2009) did not provide additional
clarification on the histological subtypes, stating that "there is sufficient evidence in humans for
the carcinogenicity of 1,3-butadiene" and that "butadiene causes cancer of the haematolymphatic
organs." Assuming that the earlier diagnoses were correct, the types of leukemias in the
University of Alabama study that showed significant dose-related associations with butadiene
exposure were CLL and CML. Increases in other NHLs such as reticulosarcoma and
endothelioma seen in other studies were also provided as supportive evidence. Neither of these
two types of leukemia has been commonly seen in leukemias induced by most other alkylating
agents (see Table 7). It should be noted that increases in CLL and NHL have been reported with
ethylene oxide exposure.
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8.4. FORMALDEHYDE (summarized primarily from IARC, 2006, unless otherwise
indicated)
Formaldehyde is a common industrial chemical, an environmental contaminant, and an
endogenous metabolite. It has been shown to induce cancer in rats and humans. Formaldehyde
is a reactive chemical that primarily binds to sulfhydryl and amine groups in polypeptides and
proteins. However, it can also form DNA-protein crosslinks, which have been shown to be
associated with its cytotoxic and genotoxic effects. It has also been shown to bind weakly to
DNA forming monoadducts and DNA-DNA crosslinks (Lu et al., 2010). Formaldehyde also
binds readily to reduced glutathione, forming a hemithioacetal that can be converted to formate
by formaldehyde dehydrogenase.
Formaldehyde has exhibited genotoxic and mutagenic effects in a large number of
experimental systems. In vitro, it has been shown to induce mutations in bacteria and
mammalian cells, DNA-protein crosslinks and strand breaks, and chromosomal aberrations. In
rodent models, it has been shown to induce DNA adducts, DNA-DNA and DNA-protein
crosslinks, chromosome aberrations, and micronuclei, primarily at the site of exposure. Genetic
damage has not typically been seen in the bone marrow or other locations distal from the site of
exposure. Occasional reports of systemic effects are found in the literature, but these have not
been seen in most studies.
One of the tumor types induced by formaldehyde in rats is squamous-cell nasal
carcinoma. Tp53 mutations were seen in 5 of 11 carcinomas isolated from the formaldehyde-
exposed rats. However, because the types of mutation seen in the nasal tumors differed from
those seen in other model systems, the principal author of the study suggested that the observed
mutations may have been due to an indirect effect, possibly occurring as a result of inflammation
and regenerative cell proliferation in the nasal passages of the exposed rats (Recio, 1997).
Formaldehyde-exposed workers have been reported to exhibit increased frequencies of
DNA-protein crosslinks in their peripheral blood lymphocytes. Increased frequencies of
micronuclei were reported to occur in the nasal and oral mucosa of formaldehyde-exposed
workers but were not seen in the oral mucosal cells of volunteers exposed to variable levels of
formaldehyde under controlled exposure conditions (Speitet al., 2007). Similarly, while negative
results were reported in some studies, others have reported that formaldehyde-exposed workers
had increased frequencies of structural chromosome aberrations and SCEs in their peripheral
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blood lymphocytes (IARC, 2006; Zhanget al., 2009). Formaldehyde exposure has not typically
been associated with hematotoxicity in humans (or animals). The mixed results seen in the
various studies may be explained, in part, by differences in exposure levels. Recently, a
biomonitoring study was conducted on a group of Chinese workers with particularly high
formaldehyde exposures (median 8-hour time weighted average exposure level of 1.28 ppm
[Zhanget al., 2010]). The researchers found that the exposed workers had lower blood cell
counts and that peripheral stem/progenitor cells obtained from the workers exhibited elevated
frequencies of monosomy for chromosome 7 and trisomy for chromosome 8—cytogenetic
alterations commonly seen in human leukemias.
In its 2006 evaluation of formaldehyde (IARC, 2006), the working group concluded that
"there is sufficient evidence in humans for the carcinogenicity of formaldehyde" based on the
occurrence of nasopharyngeal cancer. With regards to leukemia, the working group concluded
that "there is strong but not sufficient evidence for a causal association between leukaemia and
occupational exposure to formaldehyde." They felt at that time that it was "not possible to
identify a mechanism for the induction of myeloid leukaemia in humans by formaldehyde." In
the more recent 2009 evaluation (Baanet al., 2009; IARC, 2009), the new working group
concluded that "the epidemiological evidence on leukaemia has become stronger, and new
mechanistic studies support a conclusion of sufficient evidence in humans. This highlights the
value of mechanistic studies, which in only 5 years, have replaced previous assertions of
biological implausibility with new evidence that formaldehyde can cause blood-cell
abnormalities that are characteristic of leukaemia development." However, it should be noted
that this conclusion was controversial as the working group was almost evenly split on the
evaluation, with a slight majority seeing the evidence as sufficient for carcinogenicity, and the
minority viewing the evidence as limited. A recent compilation and meta-analysis of
formaldehyde-induced leukemia studies have indicated that formaldehyde exposure is most
closely associated with myeloid leukemias, primarily AML (Zhanget al., 2009).
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9. RISK ASSESSMENT IMPLICATIONS
As indicated above, approximately 25% of the agents established by IARC as human
carcinogens induce lymphohematopoietic cancers, and approximately 22% are associated with
the induction of leukemia, primarily AML. These agents have a wide variety of uses, and given
their established carcinogenic effects, they have been the focus of many risk assessments and
safety evaluations. For some of these carcinogens such as benzene or ionizing radiation, these
assessments and their refinements have been ongoing for decades and involve large amounts of
information. The sections below focus on how mechanistic information on these carcinogenic
agents can be used to inform risk assessment decisions. The following discussion is not intended
to be comprehensive but rather will focus on some key issues related to contemporary risk
assessment discussions. .
9.1. HAZARD IDENTIFICATION
Hazard identification is the process by which hazardous substances—carcinogenic agents
in this case—are identified and characterized. According to the IARC Preamble (IARC, 2008d),
which describes the IARC groupings and the weight-of-evidence decision-making process, the
Group I category "is used when there is Sufficient Evidence of Carcinogenicity in humans.
Exceptionally, an agent may be placed in this category when evidence of carcinogenicity in
humans is less than sufficient but there is Sufficient Evidence of Carcinogenicity in experimental
animals and strong evidence in exposed humans that the agent acts through a relevant
mechanism of carcinogenicity." Ethylene oxide represents one of the exceptional agents, which
was classified based on less than sufficient evidence in humans but with sufficient evidence in
animals.
The Group 2A agents represent chemicals that are probable human carcinogens for which
there "is Limited Evidence of Carcinogenicity in humans and Sufficient Evidence of
Carcinogenicity in experimental animals. In some cases, an agent may be classified in this
category when there is Inadequate Evidence of Carcinogenicity in humans and Sufficient
Evidence of Carcinogenicity in experimental animals and strong evidence that the carcinogenesis
is mediated by a mechanism that also operates in humans. Exceptionally, an agent may be
classified in this category solely on the basis of Limited Evidence of Carcinogenicity in humans.
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An agent may be assigned to this category if it clearly belongs, based on mechanistic
considerations, to a class of agents for which one or more members have been classified in
Group 1 or Group 2A " Most of the Group 2A agents listed in Table 8 have mechanisms of
action such as mutagenicity that are commonly associated with carcinogenesis. However, they
have not been adequately studied in humans, or for many of the chemotherapeutic agents, they
were administered in combination therapy often with other carcinogenic agents so that the
carcinogenic effects for the agent being investigated cannot be separately identified.
For most of the evaluations, studies of cancer in humans and animals have played the
primary role in the IARC classification. Information on the mechanism of action has typically
only played a supportive role. As a result, it is reasonable to examine information on the
mechanisms of action of the Group 1 and 2A carcinogens to help identify carcinogens and
improve the hazard identification process. Below are several observations about how
mechanistic information has and may be used in hazard identification for leukemia-inducing
agents.
9.1.1. Utility of Short-Term Genotoxicity Tests
As seen in Table 8, most of the agents identified by IARC as human carcinogens are
likely to act through a mutagenic mode of action. The majority of the Group 1 and 2 A
carcinogens are alkylating agents, but other classes of genotoxic agents such as topoisomerase II
inhibitors or nucleotide analogs are also present. The majority of the Group 1 and 2A leukemia-
and lymphoma-inducing agents are active in short-term tests both in vitro (with metabolic
activation as needed) and in vivo (IARC, 1987a). This is not surprising given their mechanisms
of action. The exceptions to this tend to be the infectious agents and the immunosuppressive
agents that act through nongenotoxic or indirect genotoxic mechanisms of action.
As also shown in Table 7, most of the leukemia-inducing agents have been shown to
induce chromosomal aberrations or micronuclei in the peripheral blood lymphocytes of exposed
humans (and animals). In addition, at commonly used and frequently high doses, these agents
also cause significant bone marrow toxicity with noticeable decreases in blood cell counts of the
exposed individuals. There are a few Group 1 agents that are exceptions and do not manifest
these particular patterns. Ethylene oxide and butadiene have not been reported to induce
hematotoxicity in humans, and butadiene has not been shown to induce structural chromosome
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aberrations in exposed workers. These two are also somewhat unusual in that the types of
cancers associated with their exposure are CLL and NHL, neoplasms that originate in mature B
lymphoid cells.
9.1.2. Usefulness of Animal Bioassays
There is substantial evidence to indicate that chronic animal bioassays are effective in
detecting human carcinogens. As described in the IARC Preamble (IARC, 2008d), "all known
human carcinogens that have been studied adequately for carcinogenicity in experimental
animals have produced positive results in one or more animal species." However, as further
noted in the Preamble, "although this association cannot establish that all agents that cause
cancer in experimental animals also cause cancer in humans, it is biologically plausible that
agents for which there are Sufficient Evidence of Carcinogenicity in experimental animals also
present a carcinogenic hazard to humans." Accordingly, the vast majority of the Group 1
leukemia- and lymphoma-inducing agents shown in Table 7 have been reported previously to be
carcinogenic in rodent bioassays (Eastmond, 1997). Indeed, many of them have been shown to
induce leukemias or lymphomas in mice and in rats. Most of these have been shown to occur in
mice and were T-cell leukemias or lymphomas, rather than the ANLL, which is prevalent in
humans. As a result, there appears to be fundamental differences between the types of
lymphohematopoietic tumors induced in humans and rodents. The reason for this remains
unknown but may be related to species differences in hematopoiesis and/or immune surveillance
(Eastmond, 1997).
The good correlation seen for animals and humans mentioned above was based primarily
on the results for chemical carcinogens and probably does not hold for many of the infectious
agents, which are likely to only infect humans and closely related species. In addition, it is not
clear at this point if this correlation will hold true for the topoisomerase II inhibitors, as most of
them have not been adequately tested in experimental animals. While the fusion gene products
have clearly been shown to affect hematopoiesis and can cause leukemias in mice (Corralet al.,
1996; Dobsonet al., 1999; Lavauet al., 2000; Forsteret al., 2003; Soet al., 2003), it is not certain
if the genes are located in regions in the rodents that will allow the same chimeric genes to be
formed. It should also be noted that the Group 2A carcinogens are also positive in rodent
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bioassays; however, this is to be expected, as this characteristic is one of the primary reasons that
the chemicals have been listed.
9.1.3. Combining Different Types of Lymphohematopoietic Cancers for Analysis
In evaluating epidemiological studies, a decision has to be made about which specific
types of disease should be combined for the analysis. Often the reporting of leukemias has been
grouped into the four common categories of AML, CML, ALL, and CLL. Similarly, the
lymphomas and myelomas have been grouped into NHL (lymphosarcoma, reticulosarcoma, and
other malignant neoplasms of lymphoid and histocytic tissue), Hodgkin's disease, and multiple
myeloma (MM). More recent case-control studies of lymphoma have expanded the NHL
grouping to include CLL, or to group lymphomas by cell type or by specific International
Classification of Disease-Oncology category (e.g., diffuse lymphatic B-cell lymphoma, follicular
lymphoma, etc.). However, many different types of groupings have been used in analyzing
epidemiological data, primarily reflecting the classification system in use at the time of diagnosis
or cause of death. An illustration of the various types of groupings used for studies of benzene
has been described by (Savitz and Andrews, 1997). In addition, evaluations of the induction of
lymphohematopoietic diseases by an agent over time can be challenging due to changes in
diagnosis, the names of diseases, and classification schemes, as well as lack of detailed case and
exposure information. Other issues such as misclassification errors and insufficient information
on death certificates can also influence the outcome of the studies. The decision about how to
analyze the data can also have a significant influence on the outcome of the analysis and the
conclusions of the study.
As illustrated in Tables 1-3, there are a large number of distinct lymphohematopoietic
cancers. By analyzing each separately, a study would only have the power to detect cancers that
were very strongly associated with exposure to an agent if detection was even possible. In
addition, the large number of comparisons could lead to some associations being labeled as
significant due simply to random chance. As a result, it is common to combine specific
lymphohematopoietic cancers for analysis. The key question, which has not fully been
answered, is which categories of specific cancer should be combined for analysis. The value of
combining uncommon lymphohematopoietic cancers has been demonstrated by Savitz and
Andrews for benzene (Savitz and Andrews, 1996; Savitz and Andrews, 1997). Benzene
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exposure is strongly associated with ANLL. However, its association with lymphoid cancers has
been a source of ongoing discussion. Savitz and Andrews showed that by analyzing non-AML
cancers together, a significant association between benzene exposure and these cancers could
also be shown. IARC, in its most recent evaluation, has given more credence to an association
between benzene and other lymphohematopoietic cancers as it concluded that there was
evidence, albeit limited, for an association between benzene and ALL, CLL, NHL, and multiple
myeloma (Baanet al., 2009; IARC, 2009). These results suggest that benzene can target the
hematopoietic stem and progenitor cells as well as more mature lymphoid cells.
In addition to combining specific types of cancers for analysis during individual studies,
it may be informative to see how various authoritative bodies such as IARC, the National
Academies of Science Biological Effects of Ionizing Radiation (BEIR) committee, and the
United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) have
combined the lymphohematopoietic cancers in making decisions about risk or for weight-of-
evidence determinations for various leukemogenic agents. As indicated above for benzene,
IARC chose to evaluate the major types of cancer separately. However, it is likely that the
association between benzene and one type of cancer provided supportive evidence that benzene
could be associated with another type of lymphohematopoietic cancer. This type of supporting
evidence appears to have played an important role in the evaluations of butadiene where
associations with CML, CLL, and to some degree, NHL, were combined in concluding that
butadiene exposure caused cancer of the "haematolymphatic organs." Similarly, information on
associations with different types of lymphohematopoietic cancers contributed to the recent IARC
evaluation on formaldehyde (AML and CML) and ethylene oxide (NHL, MM, and CLL). It
should be noted that for butadiene and probably benzene, supportive evidence came from
associations with both myeloid and lymphoid tumors.
In recent evaluations of ionizing radiation, it has been common to use all leukemias or
combine the results for ALL, AML, and CML in modeling the data and assessing cancer risks
(UNSCEAR, 2000a,b; NRC, 2006 and references therein). Increases in CLL have not been seen
in radiation-exposed study groups. When presenting the study results, the radiation-induced
leukemias are frequently described in various documents as simply leukemias or non-CLL
leukemias.
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Thus, as illustrated in the evaluation of the various cancer-inducing agents, there is no
strict consensus on how specific lymphohematopoietic cancers should be combined for analysis
and weight-of-evidence determinations. As discussed above, a variety of combinations including
those combining acute and chronic myeloid neoplasms as well as lymphoid and myeloid
neoplasms have been used in recent evaluations.
9.1.4. Potential Influence of Latency Period in Identifying Leukemogens
The period between the initial exposure to a carcinogenic agent and the onset of cancer is
known as the latency period. Latency periods for leukemias tend to be much shorter than those
seen for other induced cancers such as lung cancer induced by tobacco smoke, which has a
median latency period of approximately 30 years (Weiss, 1997). As indicated above, the latency
period for topoisomerase II inhibitors is quite short with median latency periods of 2-3 years.
For radiation and chemical chemotherapy agents, the induced leukemias first appear 1-2 years
after the beginning of treatment. The median incidence peaks at about 4-7 years, and by 10-15
years after the beginning of treatment, the incidence has frequently declined to control or near
control levels (Casciato and Scott, 1979; Pedersen-Bjergaardet al., 1987; Kaldoret al., 1990;
Davies, 2000; Schonfeldet al., 2006). This indicates that for leukemogens such as the
chemotherapeutic alkylating agents, the risk of developing t-AML will most likely peak at -4-7
years after the beginning of exposure and will begin to decline with additional follow-up.
Continuing follow-up beyond 10 to 15 years after treatment would be expected to significantly
reduce associations between exposure and leukemia and cause a bias in results towards no effect.
Hence, adding person-years after exposure ends or is substantially reduced, as sometimes occurs
in occupational studies, may significantly weaken true associations between exposure and the
incidence of leukemia. The influence of latency or time since first exposure has been clearly
demonstrated for benzene (Rinskyet al., 2002; Silveret al., 2002) and has been postulated to have
had an influence on recent formaldehyde results (Beane Freemanet al., 2009). Failure to account
for latency period for weak carcinogens or under conditions of modest exposure for potent
carcinogens could reduce the association so that the agent or exposure would no longer be
considered carcinogenic. One note of caution is that the described latency periods have typically
been seen with high doses of the leukemia-inducing agents. There is evidence that the latency
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period can be significantly influenced by the administered dose with higher doses producing
shorter latency periods and lower doses producing longer latency periods (Cadmanet al., 1977).
9.1.5. Metabolism and Bioactive Dose at the Target Organ
One of the fundamental principles of toxicology is that the toxicological response is
related to the dose of the bioactive agent in the target tissue. However, the tissue dose of the
bioactive agent may differ significantly from the external exposure dose. For many carcinogens,
even if exposure occurs, the chemical may not arrive at the target organ in a form that enables it
to exert a toxic or mutagenic effect due to pharmacokinetic or metabolic reasons. In fact, this is
a fundamental difference between the risk assessment of ionizing radiation and chemical
leukemogens. Because of its ability to directly penetrate tissues, radiation risk estimates are
almost always based on the dose of radiation that reaches the bone marrow. In contrast, risks for
chemical leukemogens such as benzene, butadiene, or ethylene oxide are typically based on the
exposure dose and may not accurately reflect the bioactive dose that reaches the bone marrow.
Studies have also shown that pharmacokinetic and metabolic factors can significantly
influence the risks from leukemia-inducing agents. For example, the peak plasma concentrations
of melphalan have been shown to vary by over 50-fold after oral dosing due to variability in
absorption, first pass metabolism, and rapid hydrolysis (GlaxoSmithKline, 2007). Indeed, for a
few patients, detectable plasma levels of melphalan were not seen even after the administration
of a high dose (1.5 mg/kg) of the drug (Choi et al., 1989). The differences in plasma
concentration would undoubtedly have an effect on its efficacy as well as its risk of inducing
t-AML.
Metabolism has been shown to exert a major effect on the mutagenic and carcinogenic
risks of leukemia-inducing agents. For example, as discussed earlier, ethylene oxide is highly
genotoxic and mutagenic in vitro. Yet, in vivo, it is a relatively weak mutagen and carcinogen as
compared to other alkylating agents (Vogel et al., 1998). It should be noted that most of the
alkylating agents used for comparison were antineoplastic drugs designed to be highly toxic.
This is likely due to the efficient metabolism of the reactive epoxide by epoxide hydrolases,
glutathione transferases, and other detoxification enzymes as well as efficient repair of the
induced adducts. Similarly, bioactivation of leukemogens such as butadiene, benzene, and
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cyclophosphamide to their reactive metabolites has been shown to significantly influence the
toxicity and genotoxicity of these agents.
9.1.6. DNA-Adduct Type, Metabolism, and Repair
The type of DNA adducts formed and their repair can have a major impact on the
toxicity, mutagenicity, and probably the cancer risk of leukemia-inducing agents. As indicated
earlier, three major classes of alkylating agents have been identified that have significantly
different mutagenic and carcinogenic potencies (Vogelet al., 1998). Category 1 agents were
mono-functional alkylating agents such as ethylene oxide and methyl methane sulfonate, which
primarily react at the N7 and N3 moieties of purines in DNA. These adducts are efficiently
repaired, and as a result, these agents tend to be relatively weak mutagens and carcinogens with
higher doses associated with observed increases in tumors in animals. Category 2 agents such as
procarbazine and ENU induce O-alkyl adducts and A-alkyl adducts in DNA, which are often
involved in base pairing and are slowly repaired. These agents are generally potent mutagens
and carcinogens. Category 3 agents such as melphalan and busulfan induce DNA breaks and
structural aberrations through their ability to cross-link DNA. They are highly toxic, mutagenic,
and carcinogenic. As indicated above, butadiene can be metabolized to diepoxybutane, a cross
linking agent, so it is classified as a Category 3 agent. However, its potency for rats and
probably humans has been reported to be much lower that the other Category 3 agents. This is
probably due to the need for metabolism as indicated above as well as the nature of the adducts
formed by butadiene. The butadiene crosslinks tend to be intrastrand and are more efficiently
repaired. Consistent with this explanation is the fact that diepoxybutane is believed to be the
reactive intermediate formed from treosulfan, a chemotherapeutic agent that appears to be
somewhat less potent in inducing t-AML in humans than other Category 3 chemotherapeutic
agents when considered on a mg/kg-basis (Kaldoret al., 1990). Interestingly, it should be noted
that treosulfan administration to humans has been associated with AML whereas occupational
exposure to 1,3-butadiene has been associated with CLL and CML. One possible explanation is
that the epoxybutene metabolite may play a more important role than diepoxybutane in inducing
the butadiene-related leukemias in humans.
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9.1.7. Individual Susceptibility
Many factors such as age, sex, genetic composition, and general health status have been
shown to influence susceptibility to leukemia-inducing agents. For example, age has been
shown to be a factor in susceptibility to radiation-induced leukemia. Studies of the atomic bomb
survivors, who were exposed to both gamma, and to a lesser extent, neutron radiation, indicated
that the highest leukemia risks were seen in children (Prestonet al., 1994, 2004). The leukemia
risk also decreased more rapidly in children as compared to those in older age groups (Prestonet
al., 1994). Interestingly, a similar increased susceptibility has not been seen for children treated
with alkylating agent-based chemotherapy as their leukemia risks do not appear to be greater
than those seen in adults, and in some cases, may be less (Levine and Bloomfield, 1992; Pyattet
al., 2005, 2007). However, direct comparisons are difficult as in most studies children and adults
have been treated with different therapeutic regimens. For the nontherapeutic classes of
leukemia-inducing agents, little is known about the relative susceptibility of children to
leukemia, as the critical studies have almost always been conducted on adults. However, a
number of studies on related biomarkers have indicated that children or adolescents are also
susceptible to the toxic and genotoxic effects of these leukemogenic chemicals (Aksoyet al.,
1974; Aksoy, 1988; Niazi and Fleming, 1989; Neriet al., 2006).
Genetic polymorphisms in genes coding for xenobiotic metabolizing enzymes, DNA-
metabolizing or repair enzymes, and drug transporter proteins are other factors that have been
implicated as significantly influencing an individual's risk of developing leukemia when exposed
to genotoxic agents. A considerable number of studies have been conducted to identify enzymes
involved in the bioactivation and the inactivation of carcinogenic agents (for reviews, see
Cheoket al. [2006], Leoneet al. [2007, 2010], and Guillem and Tormo [2008]). As discussed
above and in the review articles, significant associations have been seen for a number of genes
coding for xenobiotic metabolizing enzymes, DNA-metabolizing and repair enzymes, and drug
transporters. Individuals with genes coding for nonfunctional or less active copies of various
glutathiones-transferases, CYP3A4, and NQOl have been reported to be at increased risk for
developing t-AML following chemotherapy. Similar increased risks have been seen for
individuals that lack efficient DNA-metabolizing or repair enzymes such as enzymes involved in
nucleotide excision repair or mismatch repair. However, further research in this area is needed
as similar associations for the metabolizing enzymes and DNA-repair enzymes have not been
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seen in other studies. As discussed by Lutz and colleagues, from a population risk perspective,
the increased susceptibility associated with the various genetic polymorphisms can have a
significant impact on cancer risks, particularly among those exposed to lower doses (Lutz, 1990,
2001).
9.1.8. Summary
As evident from Table 8 and from the above discussion, leukemia-inducing agents act
through different mechanisms to induce their carcinogenic effects. While most of these are
likely to act through a mutagenic mode of action, different leukemogens have different potencies
and different associated risks, which appear to be significantly influenced by the specific
mechanisms involved. Even among the alkylating agents, different chemicals can have different
potencies that are likely due to the nature of the DNA adducts formed and their repair as well as
metabolic and pharmacokinetic factors. In addition, polymorphisms in genes related to
xenobiotic metabolism and DNA repair can lead to increased susceptibility among groups in the
population.
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Table 1. Simplified classification of the major lymphohematopoietic
neoplastic diseases in humans based largely on the French-American-British
(FAB) classification
I. Neoplasms of multipotent stem cell origin
Chronic myelogenous leukemia
II. Neoplasms possibly originating in the multipotent stem cell
Myelodysplastic syndromes
Refractory anemia
Refractory anemia with ring sideroblasts
Refractory anemia with excess blasts
Chronic myelomonocytic leukemia
Refractory anemia with excess blasts in transformation
Chronic myeloproliferative disorders
III. Neoplasms originating in stem cells or myeloid-committed precursors
Acute myeloid leukemia or acute nonlymphocytic leukemia AML/ANLL
Acute myeloblastic leukemia with minimal differentiation MO
Acute myeloblastic leukemia without maturation Ml
Acute myeloblastic leukemia with maturation M2
Acute promyelocytic leukemia M3
Acute myelomonocytic leukemia M4
Acute monocytic leukemia M5
Acute erythroleukemia M6
Acute megakaryoblastic leukemia M7
Malignant histiocytosis
IV. Neoplasms of lymphoid-committed precursors
Immature phenotype: Acute lymphoblastic leukemia ALL, L1,L2
B-cell lineage b-ALL
T-cell lineage t-ALL
Intermediate or mature phenotype: non-Hodgkin's lymphoma NHL
Nodal/splenic phase
Leukemic phase
B-cell lineage
non-Burkitt's
Burkitt's L3
T-cell lineage
Lymphoblastic lymphoma
Adult T-cell leukemia/lymphoma
Mature lymphocytic phenotype
Prolymphocytic leukemia
Chronic lymphocytic leukemia CLL
B-cell lineage
T-cell lineage
Hairy cell leukemia
Plasmacytoid phenotype: Marrow-phase predominant
Macroglobulinemia
CML
MDS
RA
RARS
RAEB
CMML
RAEB
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Heavy chain diseases
Myeloma
Hodgkin's Lymphoma
Adapted from Sullivan (1993).
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Table 2. WHO classification of myeloid and related neoplasms
MYELOPROLIFERATIVE NEOPLASMS (MPNs)
Chronic myelogenous leukemia, BCR-ABL1-positive
Chronic neutrophilic leukemia
Polycythemia vera
Primary myelofibrosis
Essential thrombocythemia
Chronic eosinophilic leukemia, not otherwise specified
Mastocytosis
Cutaneous mastocytosis
Systemic mastocytosis
Mast cell leukemia
Mast cell sarcoma
Extracutaneous mastocytoma
Myeloproliferative neoplasms, unclassifiable
MYELOID AND LYMPHOID NEOPLASMS ASSOCIATED WITH EOSINOPHILIA
AND ABNORMALITIES OF PDGFRA, PDGFRB, OR FGFR1
Myeloid and lymphoid neoplasms with PDGFRA rearrangement
Myeloid neoplasms with PDGFRB rearrangement
Myeloid and lymphoid neoplasms with FGFR1 abnormalities
MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN)
Chronic myelomonocytic leukemia
Atypical chronic myeloid leukemia, BCR-ABL1-negative
Juvenile myelomonocytic leukemia
Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Refractory anemia with ring sideroblasts and thrombocytosis (provisional entry)
MYELODYSPLASTIC SYNDROME (MDS)
Refractory cytopenia with unilineage dysplasia
Refractory anemia
Refractory neutropenia
Refractory thrombocytopenia
Refractory anemia with ring sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory anemia with excess blasts
Myelodysplastic syndrome with isolated del(5q)
Myelodysplastic syndrome, unclassifiable
Childhood myelodysplastic syndrome
Refractory cytopenia of childhood (provisional entry)
ACUTE MYELOID LEUKEMIA AND RELATED NEOPLASMS
Acute myeloid leukemia with recurrent genetic abnormalities
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
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AML with inv(l6)(p 13.1;q22) or t(l6; 16)(p 13.1 ;q22); CBFB-MYH11
APL with t(15;17)(q22;ql2); PML-RARA
AML with t(9; 11)(p22;q23); MLLT3-MLL
AML with t(6;9)(p23;q34); DEK-NUP214
AML with inv(3)(q21;q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
AML (megakaryoblastic) with t( 1;22)(p 13;q 13); RBM15-MKL1
AML with mutated NPM1 (provisional entry)
AML with mutated CEBPA (provisional entry)
Acute myeloid leukemia with myelodysplasia-related changes
Therapy-related myeloid neoplasms
Acute myeloid leukemia, not otherwise specified
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic/monocytic leukemia
Acute erythroid leukemia
Pure erythroid leukemia
Erythrol eukemi a, erythroi d / my el oi d
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
Transient abnormal myelopoiesis
Myeloid leukemia associated with Down syndrome
Elastic plasmacytoid dendritic cell neoplasm
ACUTE LEUKEMIAS OF AMBIGUOUS LINEAGE
Acute undifferentiated leukemia
Mixed phenotype acute leukemia with t(9;22)(q34;ql 1.2); BCR-ABL1
Mixed phenotype acute leukemia with t(v;l lq23); MLL rearranged
Mixed phenotype acute leukemia, B-myeloid, NOS
Mixed phenotype acute leukemia, T-myeloid, NOS
Natural killer (NK) cell lymphoblastic leukemia/lymphoma (provisional entry)
Source: WHO (2008).
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Table 3. WHO classification of lymphoid neoplasms
PRECURSOR LYMPHOID NEOPLASMS
B lymphoblastic leukemia/lymphoma
B lymphoblastic leukemia/lymphoma, NOS
B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
B lymphoblastic leukemia/lymphoma with t(9;22)(q34;ql \.2),BCR-ABL 1
B lymphoblastic leukemia/lymphoma with t(v;l lq23);MZX rearranged
B lymphoblastic leukemia/lymphoma with t(12;21)(pl3;q22) TEL-AML1
(.ETV6-RUNX1)
B lymphoblastic leukemia/lymphoma with hyperdiploidy
B lymphoblastic leukemia/lymphoma with hypodiploidy
B lymphoblastic leukemia/lymphoma with t(5; 14)(q31 ;q32) IL3-IGH
B lymphoblastic leukemia/lymphoma with t(l;\9)(q23;pl3.3);TCF3-PBXl
T lymphoblastic leukemia/lymphoma
MATURE B-CELL NEOPLASMS
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Splenic marginal zone lymphoma
Hairy cell leukemia
Splenic B-cell lymphoma/leukemia, unclassifiable (provisional entry)
Splenic diffuse red pulp small B-cell lymphoma (provisional entry)
Hairy cell leukemia—variant (provisional entry)
Lymphoplasmacytic lymphoma
Waldenstrom macroglobulinemia
Heavy chain diseases
Alpha-heavy chain disease
Gamma-heavy chain disease
Mu heavy chain disease
Plasma cell myeloma
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-
lymphoma)
Nodal marginal zone B-cell lymphoma
Pediatric nodal marginal zone lymphoma (provisional entry)
Follicular lymphoma
Pediatric follicular lymphoma (provisional entry)
Primary cutaneous follicle center lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma (DLBCL), NOS
T-cell/histiocyte-rich large B-cell lymphoma
Primary DLBCL of the CNS
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Primary cutaneous DLBCL, leg type
EBV positive DLBCL of the elderly (provisional entry)
DLBCL associated with chronic inflammation
Lymphomatoid granulomatosis
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
ALK-positive large B-cell lymphoma
Plasmablastic lymphoma
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
Primary effusion lymphoma
Burkitt lymphoma/leukemia
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell
lymphoma and Burkett lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell
lymphoma and classical Hodgkin lymphoma
MATURE T-CELL AND NK-CELL NEOPLASMS
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Chronic lymphoproliferative disorder of NK cells (provisional entry)
Aggressive NK-cell leukemia
Systemic EBV-positive T-cell lymphoproliferative disease of childhood
Hydroa vacciniforme-like lymphoma
Adult T-cell leukemia/lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides
Sezary syndrome
Primary cutaneous CD30-positive anaplastic large cell lymphoma
Lymphomatoid papulosis
Primary cutaneous anaplastic large cell lymphoma
Primary cutaneous gamma-delta T-cell lymphoma
Primary cutaneous CD8 positive aggressive epidermotropiccytotoxic T-cell lymphoma
(provisional entry)
Primary cutaneous CD4 positive small/medium T-cell lymphoma
Peripheral T-cell lymphoma, NOS (provisional entry)
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, ALK positive
Anaplastic large cell lymphoma, ALK positive (provisional entry)
HODGKIN LYMPHOMA
Nodular lymphocyte predominant Hodgkin lymphoma
Classical Hodgkin lymphoma
Nodular sclerosis classical Hodgkin lymphoma
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Lymphocyte-rich classical Hodgkin lymphoma
Mixed cellularity classical Hodgkin lymphoma
Lymphocyte-depleted classical Hodgkin lymphoma
HISTIOCYTIC AND DENDRITIC-CELL NEOPLASMS
Histiocytic sarcoma
Langerhans cell histiocytosis
Langerhans cell sarcoma
Interdigitating dendritic cell sarcoma
Follicular dendritic cell sarcoma
Fibroblastic reticular cell tumor
Indeterminate dendritic cell tumor
Disseminated juvenile xanthogranuloma
POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS (PTLD)
Early lesions
Plasmacytic hyperplasia
Infectious mononucleosis-like PTLD
Polymorphic PTLD
Monomorphic PTLD (B- and T/NK-cell types)
Classical Hodgkin lymphoma type PTLD
Source: WHO (2008).
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Table 4. Cytogenetic comparisons of de novo leukemias and t-AML1
AML
de novo
t-AML
Cytogenetic features
n = 3649 (%)
n = 581 (%)
Number of anomalies
1 anomaly
2186 (60)
242 (42)
2 anomalies
641 (18)
104 (18)
>3 anomalies
822 (23)
235 (40)
Ploidy level
hypodiploid
813 (22)
224 (39)
pseudodiploid
1843 (51)
242 (42)
hyperdiploid
974 (27)
108 (19)
tri-/tetraploid
13 (0.4)
7(1.2)
unknown ploidy
6 (0.2)
0
Unbalanced anomalies
2734 (75)
491(85)
3p-
33 (0.9)
17 (2.9)
-5
152 (4.2)
73 (13)
5q-
249 (6.8)
77(13)
—7
340 (9.3)
167 (29)
-7 (sole)
114 (3.1)
51 (8.8)
7q-
147 (4.0)
36 (6.2)
der( 1 ;7)
8 (0.2)
12(2.1)
loss of 5 and/or 7
717 (20)
284 (49)
+8
614 (17)
84(14)
+8 (sole)
269 (7.4)
19(3.3)
llq—
82 (2.2)
17 (2.9)
der(12p)
153 (4.2)
37 (6.4)
13q—
32 (0.9)
7(1.2)
—17
172 (4.7)
53 (9.1)
der(17p)
104 (2.9)
36 (6.2)
-18
129 (3.5)
40 (6.9)
20q—
45 (1.2)
13 (2.2)
—21
92 (2.5)
41 (7.1)
Balanced anomalies
1713 (47)
215 (37)
t(l;3)(p36;q21)
2(0.1)
3 (0.5)
inv(3)(q21q26)b
26 (0.7)
1 (0.2)
t(6;ll)(q27;q23)
7 (0.2)
2 (0.3)
t(6;9)(p23;q34)
18 (0.5)
1 (0.2)
t(8;16)(pl l;pl3)
10(0.3)
2 (0.3)
t(8;21)(q22;q22)
335 (9.2)
11(1.9)
t(9;l I)(p22;q23)
64(1.8)
35 (6.0)
t(9;22)(q34;ql 1)
52(1.4)
0
t( 11; 19)(q23;p 13)
16 (0.4)
14 (2.4)
t(l lq23)
144 (3.9)
72(12)
t(15;17)(q22;ql2)
388 (11)
16 (2.8)
inv(16)(pl3q22)c
144 (3.9)
4 (0.7)
t(21q22)
375 (10)
20 (3.4)
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includes 'unselected' cases from the Mitelman Database of Chromosome Aberrations in Cancer,
includes also cases witht(3;3)(q21;q26).
includes also cases witht(16;16)(pl3;q22).
Source: Mauritzsonet al. (2002). Reprinted by permission from the Nature Publishing Group.
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Table 5. Frequency of molecular mutations in de wovoAMLand
t-MDS/t-AMLa
Mutated gene
AML de novo
t-MDS/t-AML
FLT3 (ITDh)
35%
0%
FLT3 (TKD°)
9%
<1%
NRAS
10-15%
10%
K1TD816
-5%
NAd
MLL (ITDh)
3%
2-3%
RUNX1
10-15%
15-30%
TP53
10%
25-30%
PTPN11
-2%
3%
NPM1
35-50%
4-5%
CEBPA
6-15%
Rare
JAK2V617F
2-5%
2-5%
aFrom Qianet al. (2009). Reprinted with permission from Elsevier.
bITD = internal tandem duplication.
°TKD = tyrosine kinase-domain.
dNA = not available.
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Table 6. Gene mutations observed in the Copenhagen series of 140 patients
with t-MDS (« = 89) or t-AML (« = 51)a
t-MDS
t-AML
Class I mutations
Tyrosine kinases
FLT3 ITD+ point mutations
1
10
cKIT point mutations
0
2
cFMS point mutations
0
0
JAK2 point mutations
2
0
Genes in the RAS/BRAF pathway
KRAS or NRAS point mutations
7
7b
BRAF point mutations
0
3b
PTPN11 point mutations
2
2
Class II mutations
Transcription factors
AML1/CBFB chimerically rearranged
3
7
AML1 point mutations
20
2
MLL chimerically rearranged
0
11
MLL ITD
1
1
RARA chimerically rearranged
0
2
EVI1 chimerically rearranged
3
1
CEBPA point mutations
0
0
NPM1 point mutations
3
7
Tumor suppressor gene
TP53 point mutations
25
9
Total 131 mutations observed
67
64
"From Pedersen-Bjergaardet al. (2008) Reprinted with permission from the Nature
Publishing Group.
bOne patient had a mutation of KRAS together with a mutation of BRAF possibly in
different subclones.
This document is a draft for review purposes only and does not constitute Agency policy.
9/14/10 57 DRAFT—DO NOT CITE OR QUOTE
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Table 7. Characteristics of selected known and probable human leukemia- and lymphoma-inducing agents
Agents carcinogenic to humans
CAS
1°
Lymphohemato
-poetic cancer
2° limited
evidence
Myelotoxicity
Chromosomal
Aberrations"
Source(s)
DNA-reactive
1,3-Butadiene
Lympho-
hematopoietic
cancers
b
IARC, 2008a, 2009;
Baanet al., 2009
1,4-Butanediol dimethanesulfonate (Busulfan, Myleran)
55-98-1
ANLL
+
SCA
Grosseet al., 2009; IARC,
1987b
Chlorambucil
305-03-3
ANLL
+
SCA
Grosseet al., 2009; IARC,
1987b
(1 -(2-)Chlorethyl)-3 -(4-methylcyclohexyl) nitrosurea
(Methyl-CCNU, Semustine)
13909-09-6
ANLL
+
NI°
Grosseet al., 2009
Cyclophosphamide
50-18-0
ANLL
+
SCA
Grosseet al., 2009; IARC,
1987b
Ethylene Oxide
75-21-8
NHL, MM,
CLL
-
SCA
IARC, 2009, 2008b;
Baanet al., 2009
Formaldehyde
50-00-0
Myeloid
leukemias
+/-
+/-
IARC, 2009, 2006
Melphalan
148-82-3
ANLL
+
SCA
Grosseet al., 2009; IARC,
1987b
MOPP therapy
ANLL
+
SCA
Grosseet al., 2009; IARC,
1987b
Treosulfan
299-75-2
ANLL
+
NI
Grosseet al., 2009; IARC,
1987b
Thio-TEP A (tris( 1 -aziridinyl)-phosphine)
52-24-4
Leukemia
+
SCA
Grosseet al., 2009; IARC,
1987b
Topoisomerase II-inhibitor
Etoposide
33419-42-0
ANLL
+
MN
Grosseet al., 2009; IARC,
2000a
Immunosuppressive agents
Cyclosporine
79217-60-0
NHL
-
SCA
Grosseet al., 2009; IARC,
1990c
Azathioprine
446-86-6
NHL
+
SCA
Grosseet al., 2009; IARC,
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1987b
Other
Benzene
71-43-2
ANLL
NHL, ALL,
CLL, MM
+
SCA
IARC, 2009; Baanet al.,
2009
2,3,7,8-TCDD
1746-01-6
NHL
-
-
IARC, 2009
X- and Gamma-mdiation
ANLL, CML,
ALL
+
SCA
IARC, 2000b
Neutron radiation
leukemia
NI
SCA
IARC, 2000b
Thorium-232 and its decay products
ANLL, CML,
ALL
NI
SCA
El Ghissassiet al., 2009;
IARC, 2001
Phosphorus-32, as phosphate
ANLL
+
SCA
IARC, 2001
Fission products including strontium-90
Leukemia
(non-CLL)
NI
NI
El Ghissassiet al., 2009;
Krestininaet al., 2010
Tobacco smoking and tobacco smoke
ANLL
NI
SCA
IARC, 2004
Tobacco smoking (parental exposure)
Childhood
Leukemia
(ALL)
NI
NI
Secretanet al., 2009
Rubber manufacturing occupation
Leukemia,
Lymphoma
NI
SCA
IARC, 2009
Painting occupation (maternal exposure)
Childhood
leukemia
NI
NI
IARC, 2009
Infectious agents
Epstein-Barr virus
Burkitt's
lymphoma, NHL
NK/T-cell
lymphoma,
Hodgkin's
lymphoma
NI
Bouvardet al., 2009; IARC,
1997
Human immunodeficiency virus Type 1
NHL, Hodgkin's
lymphoma
+
NI
Bouvardet al., 2009; IARC,
1996a
Human T-cell lymphotrophic virus Type 1
Adult T-cell
leukemia and
lymphoma
NI
Bouvardet al., 2009; IARC,
1996b
Hepatitis C virus
NHL
-
NI
Bouvardet al., 2009
Helicobacter pylori
low-grade B-cell
-
NI
Bouvardet al., 2009
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MALT
Kaposi's sarcoma herpes virus
1° effusion
lymphoma
-
NI
Bouvardet al., 2009
Selected asents orobablv carcinosenic to humans (IARC Group 2A)
DNA-reactive
Bischloroethyl nitrosourea (BCNU; carmustine)
154-93-8
ANLL
+
NId
IARC, 1987b
1 -(2-)Chlorethyl-3 -cyclohexyl-1 -nitrosurea (CCNU;
lomustine)
13010-47-4
ANLL
+
NI
IARC, 1987b
\ - E t hvl -A- n i t ro so u re a
759-73-9
ANLL?
NI
NId
IARC, 1987b
Cisplatin
15663-27-1
leukemia
+
NId
IARC, 1987b
Nitrogen Mustard (Mechlorethamine)
51-75-2
ANLL
+
SCA
IARC, 1987b
Procarbazine
671-16-9
ANLL
+
NId
IARC, 1987b
Chlorozotocin
54749-90-5
ANLL
+
NI
IARC, 1990b
Topoisomerase II-inhibitor
Adriamycin
25316-40-9
ANLL
+
SCA
IARC, 1987b
Teniposide
29767-20-2
ANLL
+
NId
IARC, 2000c
Other
Azacytidine
320-67-2
Leukemia
+
NId
IARC, 1990a
Chloramphenicol
56-75-7
ANLL
+
NI
IARC, 2000c
aSCA = structural chromosome aberrations, MN = micronuclei.
bMyelotoxicity is either not seen or infrequently seen.
°No information located for humans.
increases seen in the blood or bone marrow of experimental animals.
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Table 8. Likely mechanisms involved in the carcinogenesis of selected known and probable human leukemia-
and lymphoma-inducing agents
Agents carcinogenic to humans (IARC Group 1 or similar)
Asent
Cancer
Class
Activation
1° Mechanism
Other
1° Source
1,3-Butadiene
Various
Industrial
chemical
Bioactivated to mono-
and bifunctional
alkylating agents
Mutation resulting from
DNA binding and/or
chromosomal alterations
Metabolized into
diepoxybutane
IARC, 2008a, 2009;
Baanet al., 2009
Busulfan (Myleran;
1,4-Butanediol
dimethanesulfonate)
ANLL
Therapeutic
agent
Direct-acting
bifunctional alkylating
agent
Mutation resulting from
DNA binding and/or
chromosomal alterations
Grosseet al., 2009
Chlorambucil
ANLL
Therapeutic
agent
Direct-acting
bifunctional alkylating
agent
Mutation resulting from
DNA binding and/or
chromosomal alterations
Grosseet al., 2009
Semustine (Methyl-CCNU;
l-(2-Chlorethyl)-3-(4-
methylcy clohexy 1) 1 -
nitrosurea)
ANLL
Therapeutic
agent
Degrades to direct-
acting alkylating and
carbamoylating agents
Mutation resulting from
DNA binding and/or
chromosomal alterations
Grosseet al., 2009
Cy clopho sphamide
ANLL
Therapeutic
agent
Bioactivated to
bifunctional alkylating
agent and acrolein
Mutation resulting from
DNA binding and/or
chromosomal alterations
Grosseet al., 2009
Ethylene oxide
Various
Industrial
chemical
Direct-acting
alkylating agent
Mutation resulting from
DNA binding and/or
chromosomal alterations
IARC, 2008b, 2009;
Baanet al., 2009
Formaldehyde
ANLL
Industrial
chemical
Direct-acting, forms
DNA-protein
crosslinks
Unknown, possibly
mutation resulting from
DNA binding and/or
chromosomal alterations
IARC, 2006, 2009;
Baanet al., 2009
Melphalan
ANLL
Therapeutic
agent
Direct-acting
bifunctional alkylating
agent
Mutation resulting from
DNA binding and/or
chromosomal alterations
Grosseet al., 2009
MOPP therapy
ANLL
Combination of
therapeutic
A direct-acting
bifunctional and an
Mutation resulting from
DNA binding and/or
Grosseet al., 2009
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agents
indirect
monofunctional
alkylating agent, a
microtubule inhibitor,
and a glucocortocoid
chromosomal alterations
Treosulfan
ANLL
Therapeutic
agent
Converts to a mono-
and bifunctional
alkylating agent
Mutation resulting from
DNA binding and/or
chromosomal alterations
Converts into
diepoxybutane, an
(intrastrand?)
crosslinking agent.
Hartleyet al., 1999;
Grosseet al., 2009
Thio-TEPA (tris(l-
aziridinyl)-phosphine)
Leukemia
Therapeutic
agent
Direct-acting
trifunctional alkylating
agent. Also,
metabolized to
monofunctional
alkylating agent
aziridine.
Mutation resulting from
DNA binding and/or
chromosomal alterations
Maanenet al., 2000;
Grosseet al., 2009
Etoposide
ANLL
Therapeutic
agent
Topoisomerase II-
poison
Mutation resulting from
chromosomal breakage
and translocations
Results in modified
transcription factor
Grosseet al., 2009
Cyclosporine
NHL
Therapeutic
agent
Inhibition of
transcription factors
that regulate inducible
cytokine expression
Immunosuppression
Grosseet al., 2009
Azathioprine
NHL
Therapeutic
agent
Metabolized into
nucleotide analog
Immunosuppression
Also genotoxic
Grosseet al., 2009
Benzene
ANLL
Industrial
chemical and
environmental
agent
Metabolized into
reactive protein and
DNA-binding species
Unknown, likely
mutation resulting from
either DNA binding,
topoisomerase II-
inhibition, and/or
oxidative damage
Likely multiple
metabolites and
modes of action
involved
Baanet al., 2009;
I ARC, 2009
2,3,7,8-TCDD
NHLa
Environmental
contaminant
Receptor-mediated
effects modifying
cellular replication and
apoptosis
Unknown, likely
immunosuppression
Also can lead to
DNA damage
through oxidative
stress
Baanet al., 2009;
I ARC, 2009;
Holsappleet al., 1996
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X- and Gamma-radiation
ANLL
CML
ALL
Therapeutic,
energy and
military uses
Direct and indirect
DNA damage
Mutation resulting from
DNA damage and/or
chromosomal alterations
I ARC, 2000b;
El Ghissassiet al.,
2009
Alpha and beta particle
emitters
ANLL
(also CML
and
ALL for Th-
32)
Therapeutic,
energy and
military uses
Direct and indirect
DNA damage
Mutation resulting from
DNA damage and/or
chromosomal alterations
I ARC, 2001; El
Ghissassiet al., 2009
Tobacco smoking and
tobacco smoke
ANLL
Lifestyle use
Direct and indirect
DNA damage
Unknown, likely
mutation resulting from
DNA binding and/or
chromosomal alterations
I ARC, 2004;
Secretanet al., 2009
Tobacco smoking (parental)
Childhood
ALL
Parental use
Direct and indirect
DNA damage
Unknown, assumed
mutation resulting from
DNA binding and/or
chromosomal alterations
occurring in germ cells
or in utero
Epigenetic changes
could also contribute
I ARC, 2004;
Secretanet al., 2009
Rubber manufacturing
occupation
Leukemia
Lymphoma
Occupational
exposure
Unknown but DNA-
reactive chemicals are
used
Unknown, assumed to be
mutation resulting from
DNA binding and/or
chromosomal alterations
and/or
immunosuppression
I ARC, 2009
Painting occupation
Childhood
leukemia3
Occupational
exposure
Unknown but DNA-
reactive chemicals are
used
Unknown, assumed
mutation resulting from
DNA binding and/or
chromosomal alterations
occurring in germ cells
or in utero
Other mechanisms
are also likely.
I ARC, 2009
Epstein-Barr virus
Burkitt's
lymphoma
NHL
NK/T-cell
lymphoma
Hodgkin's
Infectious agent
Viral infection and
expression of viral
proteins leading to
lymphocyte
transformation
Alteration in normal B-
lymphocyte function
leading to cell
proliferation, inhibition
of apoptosis, genomic
instability, and cell
Hjalgrim and Engels,
2008; Bouvardet al.,
2009
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lymphoma
migration
Human immunodeficiency
vims Type 1
NHL
Infectious agent
Viral infection and
expression of viral
proteins leading to loss
of CD 4+T
lymphocytes
Immunosuppression (as
an indirect effect)
Hjalgrim and Engels,
2008; Bouvardet al.,
2009
Human T-cell lympho trophic
vims Type 1
Adult T-cell
leukemia and
lymphoma
Infectious agent
Viral infection and
expression leading to
lymphocyte
transformation
Immortalization and
transformation of T cells
Hjalgrim and Engels,
2008; Bouvardet al.,
2009
Hepatitis C vims
NHL
Infectious agent
Viral infection and
expression of viral
proteins leading to
chronic immune
stimulation
Chronic immune
stimulation
Hjalgrim and Engels,
2008; Bouvardet al.,
2009
Helicobacter pylori
Low-grade B-
cell MALT
Infectious agent
Inflammation leading
to cellular alterations
Oxidative stress, altered
cellular turnover and
gene expression,
methvlation. and
mutation
Chronic immune
stimulation.
Hjalgrim and Engels,
2008; Bouvardet al.,
2009
Kaposi's sarcoma herpes
virus
1° Effusion
lymphoma
Infectious agent
Viral infection and
expression of viral
proteins
Cell proliferation,
inhibition of apoptosis,
genomic
instability, cell migration
Bouvardet al., 2009
Selected agents probably carcinogenic to humans (IARC Group 2A)
Bischloroethyl nitrosourea
(BCNU; carmustine)
ANLL
Therapeutic
agent
Direct-acting
bifunctional
alkylating agent.
Mutation resulting from
DNA binding and/or
chromosomal
alterations
IARC, 1987b;
Vogeletal., 1998
(1 -(2-)Chlorethy 1) -3 -
cyclohexyl-1 -nitrosurea
(CCNU; lomustine)
ANLL
Therapeutic
agent
Direct-acting
bifunctional
alkylating agent.
Mutation resulting from
DNA binding and/or
chromosomal
alterations
IARC, 1987b;
Vogeletal., 1998
TV-Ethyl - Y-nitro sourea
ANLL?
Experimental
reagent
Direct-acting
alkylating agent
Mutation resulting from
DNA binding and/or
chromosomal
alterations
IARC, 1987b;
Vogeletal., 1998
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Cisplatin
Leukemia
Therapeutic
agent
Direct-acting
bifunctional DNA
binding agent.
Mutation resulting from
DNA binding and/or
chromosomal
alterations
IARC, 1987b;
Vogeletal., 1998
Nitrogen Mustard
(Mechlorethamine)
Leukemia
Therapeutic
agent
Direct-acting
bifunctional
alkylating agent.
Mutation resulting from
DNA binding and/or
chromosomal
alterations
IARC, 1987b;
Vogeletal., 1998
Procarbazine
ANLL
Therapeutic
agent
Bioactivated to a
mono functional
alkylating agent.
Mutation resulting from
DNA binding and/or
chromosomal
alterations
IARC, 1987b;
Vogeletal., 1998
Chlorozotocin
ANLL
Therapeutic
agent
Direct-acting
bifunctional
alkylating agent.
Mutation resulting from
DNA binding and/or
chromosomal
alterations
IARC, 1987b;
Vogeletal., 1998
Adriamycin
ANLL
Therapeutic
agent
Topoisomerase II-
poison and redox-
cycling agent
Mutation resulting from
chromosomal breakage
and translocations
IARC, 1987b
Teniposide
ANLL
Therapeutic
agent
Topoisomerase II-
poison
Mutation resulting from
chromosomal breakage
and translocations
IARC, 2000c
Azacytidine
Leukemia
Therapeutic
agent
DNA-
methyltransferase
inhibitor through
metabolism and
incorporation into
DNA.
Alters DNA
methylation and gene
expression. Is also
genotoxic.
NTP, 2005;
Stresemann and
Lyko, 2008
Chloramphenicol
ANLL
Therapeutic
agent
Binds to ribosomal
subunit blocking
protein synthesis in
mitochondria.
Metabolite may also
induce DNA damage
Unknown, presumed to
be mutation resulting
from DNA damage
and/or chromosomal
alterations
NTP, 2005
aLimited Evidence
-------
Table 9. General characteristics of human leukemias and related neoplasms
induced by recognized leukemia-inducing agents
Agent
Disease3
FABa
MDSb
Typical clonal
Chromosome
Abnormalities
Latency
(yrs)c
Ionizing radiation
AML
ALL
CML
M1-M6
L1-L2
+++
-7, -5, 7q-, 5q-
t(9;22)
5-7
8
5
Alkylating agent
chemotherapeutic drugs
AML
Ml, M2
+++
-7, -5, 7q-, 5q-
~5
Ethylene oxide
{CLL}d
{NHL}
{MM}
?
"
?
?
1,3-Butadiene
{CLL}
{CML}
{NHL}
?
"
?
?
Epipodophyllotoxin
topoisomerase II
inhibitors
AML
M4, M5
+/-
t(l lq23)
2-3
Dioxopiperazine
topoisomerase II
inhibitors
AML
M2, M3
+/-
t(8;21)
t(15;17)
3
Benzene
AML
{ALL}
{CLL}
{NHL}
{MM}
Ml, M2, M6 M3
++
Mixed6
t(8;21), t( 15; 17)
<12
Formaldehyde
AML
{CML}
?
-
?
?
aSee Figure 3, for abbreviations on the types of lymphohematopoietic neoplasms and the leukemia subtypes
classified according to the French-American-British (FAB) system.
bMDS = myelodysplastic syndrome.
Approximate median latency period.
dNeoplasms in brackets indicate that there is limited evidence that they are induced by the agent.
"Clonal chromosomal abnormalities are present, but the karyotypes reported to date have been inconsistent. Two
recent reports have provided additional evidence for the involvement of t(8;21) and t(15;17) (Mondrala and
Eastmond, 2009; Wonget al., 2010).
Adapted from Eastmond (1997) and Eastmond et al. (2005) and reprinted by permission from Elsevier.
This document is a draft for review purposes only and does not constitute Agency policy.
9/14/10 66 DRAFT—DO NOT CITE OR QUOTE
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OQ o
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%
<®
so
Hematopoietic
stem cell
(pluripotent)
Multipotent
progenitor cells
Common myeloid
progenitor cell
Megakaryocyte
eiythroid
progenitor cell
Common lymphoid
progenitor cell
Granulocyte
macrophage
progenitor cell
t 4
Pro-DC Pro-T Pro-NK Pro-B
I I
I
~ I
_ip
C2>C2> °8P
Platelets Macrophages T-lymphocytes B-lymphocytes
Erythrocytes Granulocytes Dendritic cells Natural killer cells
Lineage restricted
progenitor cells
Mature hematopoietic
cells
Figure 1. Simplified model of hematopoiesis showing lineages of major types of hematopoietic cells.
-------
Childhood ALL
Cut. T lymphoma
ATL, T-PLL
Germ
line
Early embryonic
stem cells
Haemopoietic
(lympho-myeloid) stem
cells
O®
Lymphoid
stem cells
Rare AL
1
1
©
Rare AL
Adult ALUAML,
MDS, CML
O
Myeloid
stem cells
Childhood AML
1 1
©©
Mature
Lymphocyte
subsets
B-NHL
B-CLL. PLL, HCL
Myetoma
Figure 2. Hierarchical stem cell origins of leukemia and related cancers. The
arrows denote the likely level of clonal selection for the majority of the leukemia
subtypes listed.
Abbreviations: AL = acute leukemia; Cut. T lymphoma = cutaneous T-cell
lymphoma; ATL = adult T-cell leukemia; T-PLL = T-cell prolymphocyte
leukemia; B-cell non-Hodgkin lymphoma; PLL = prolymphocytic leukemia; HCL
= hairy cell leukemia. For other abbreviations, see Table 1.
Source: Greaves (1999). Reprinted by permission from Elsevier.
This document is a draft for review purposes onlv and does not constitute Agency policy.
9/14/10 68 DRAFT—DO NOT CITE OR QUOTE
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Pathway
t-MDS
t-AML
II
III
IV
VI
VII
VIII
7q./.7
n = 39
AML1
mutafcofis
r»= 15
I
Alkylating Agents
Centromeric Breakage
PAS mutations ^
pA;Ull.ta«oriS ~—
p 15 pronator
methyiation
% of cases
0 50 100 %
5q-/-5
n = 34
n - IS
71J-/-7
n= 18
pS3 mutations
n =25
17p-/-17
cornple* Kar/oVoea
MLL-AMLl Hmplilc.
Topoisomerase II Inhibitors
Chimeric Fusion Genes
7qV-7
([3:21)
21q22 invne)
AMI I CBFH
n= 10
—nSfJT mutations
1(15.17)
FtARA
nx:Z
—i _.Fir3mutaH)rs
1ip15
WPJS
Normal
karyotype
n = 9
De Novo Cases?
f)A£ rotations ~
JAKS mulalioriE
Otrors
r» = 16
Noirnal
karyotype
n= 15
Others
n = 5
PlOm.itoiiors |—
JTA3 mutations
AM.T mutations
MLL UP
34%
30%
91 %
11q23
MLL
n = 11
—) RA$ mutations ~
—| 9RAF mutations |—
50 °o
83%
33%
?%
ao%
49%
Figure 3. Genetic pathways of t-MDS and t-AML based on 140 cases from
the Copenhagen study group. The black triangle indicates significant
association with transformations from t-MDS to t-AML.
Source: Pedersen-Bjergaardet al. (2006). Reprinted by permission from
Macmillan Publishers Ltd.
This document is a draft for review purposes onlv and does not constitute Agency policy.
9/14/10 69 DRAFT—DO NOT CITE OR QUOTE
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1 REFERENCES
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