REVIEW
The Secondary Leukemias: Challenges and
Research Directions
Malcolm A. Smith, Ronald P. McCaffrey, Judith E. Karp*
Acute myelogenous leukemia (AML) arising following exposure to genotoxic agents has been recognized as a distinctive entity for more than 40 years. Secondary, or
therapy-related, AML accounts for 10%-20% of all AML
cases. This review addresses four overarching areas of investigation focused on secondary AMLs: 1) dissection of the
molecular structure of the induced genetic lesions and identification of the functional consequences of these changes,
thereby providing clues to the pathogenesis of secondary
AML and potentially serving as a basis for innovative
therapeutic interventions; 2) identification and characterization of mechanisms of DNA damage and the orderly
repair of such damage; 3) identification and application of
accurate biomarkers of leukemogenesis for the purpose of
risk prediction and quantification, potentially allowing
recognition of patients especially susceptible to the
leukemogenic effects of chemotherapy (for genetic or acquired reasons) and allowing their treatment for cancer to
be modified on the basis of this susceptibility; and 4) design
and implementation of longitudinal clinical and genetic
monitoring of high-risk populations (i.e., individuals undergoing cytotoxic therapies for primary cancers). This review
of the literature relating to these areas builds upon these
themes and attempts to synthesize these seemingly disparate
areas of research so that they can be more effectively utilized together to address the problem of secondary AML. Ultimately, the evaluation of these areas will improve our
understanding of de novo leukemia and will serve as a
springboard for the development of hew concepts of therapy
and prevention. [J Natl Cancer Inst 1996;88:407-18]
Acute myelogenous leukemia (AML) arising following exposure to genotoxic agents has been recognized as a distinctive
entity for more than 40 years. The first descriptions of these "induced" or environmental-occupational leukemias involved exposures to radiation, followed by recognition of AML cases
related to exposures to benzene and arsenicals {12).
Secondary, or therapy-related, AML accounts for 10%-20%
of all AML cases and can be viewed as a subset of environmental-occupational leukemias (3,4). AML cases occurring following cytotoxic therapy were first described 25-30 years ago,
Journal of the National Cancer Institute, Vol. 88, No. 7, April 3, 1996
concomitantly with the achievement of prolonged survival and
cures in Hodgkin's disease patients (5,6). The leukemias
evolved from a background of multiagent cytotoxic therapies
that included alkylating agents, often in combination with radiation therapy (6,7). The AML cases arising after DNA-damaging
chemotherapeutic agents and the AML cases caused by diverse
environmental factors (e.g., benzene, petroleum, organic solvents, and arsenical pesticides) are genotypically similar; the
majority are characterized by deletions of all or part of chromosomes 5 and/or 7 (3,4,8$). More recently, AML cases related to
prior treatment with epipodophyllotoxins (etoposide and
teniposide) have been identified, often having translocations involving chromosome band 1 Iq23 (8,10-12).
Secondary AML is of growing concern because of the increasing armamentarium of genotoxic drugs that damage DNA
in a variety of ways, because of the use of these genotoxic
agents in combination and at higher dose intensities, and because of the lengthening survival in many patients. To address
some of the complex issues surrounding these devastating
leukemias, the National Cancer Institute (NCI) and the
Leukemia Society of America (LSA) jointly hosted the
Workshop on Secondary Leukemias (held January 29-30, 1995,
in Bethesda, MD) to define research opportunities for elucidating mechanisms underlying the etiology and pathogenesis, the
treatment, and ultimately the prevention of secondary AML.
The workshop addressed four overarching areas for investigation: 1) dissection of the molecular structure of the induced
genetic lesions and identification of the functional consequences
of these changes, thereby providing clues to the pathogenesis of
secondary AML and potentially serving as a basis for innovative
therapeutic interventions; 2) identification and characterization
of mechanisms of DNA damage and the orderly repair of such
damage; 3) identification and application of accurate biomarkers
*Affiliations of authors: M. A. Smith (Clinical Trials Evaluation Program,
Division of Cancer Treatment, Diagnosis, and Centers), J. E. Karp (Chemoprevention Branch, Division of Cancer Prevention and Control), National Cancer Institute, Bethesda, MD; R. P. McCaffrey, Section of Medical Oncology,
Evans Department of Clinical Research, Boston University Medical Center, MA.
Correspondence to: Judith E. Karp, M.D., National Institutes of Health, Executive Plaza North, Rm. 212C, Bethesda, MD 20892.
See "Notes" section following "References."
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407
of leukemogenesis for the purpose of risk prediction and quantification, potentially allowing recognition of patients especially
susceptible to the leukemogenic effects of chemotherapy (for
genetic or acquired reasons) and allowing their treatment for
cancer to be modified on the basis of this susceptibility; and 4)
design and implementation of longitudinal clinical and genetic
monitoring of high-risk populations (i.e., individuals undergoing
cytotoxic therapies for primary cancers). This review of the
literature relating to these areas builds upon these themes and attempts to synthesize these seemingly disparate areas of research
so that they can be more effectively utilized together to address
the problem of secondary AML.
Secondary AML Following Treatment With
Alkylating Agents
Secondary AML that follows treatment with alkylating agents
has a characteristic morphologic and clinical phenotype (Table
1) (8,13). Typically, these cases present with a myelodysplastic
syndrome that culminates in an acute leukemia with a less common phenotype (M6 or M7 with concomitant myelofibrosis).
Their peak incidence is 4-6 years following the initiation of
cytotoxic therapy for the first malignancy, although they can
occur with a latent period as short as 12 months or as long as 1520 years. Chromosomes 5 and/or 7 are preferentially involved in
secondary AML cases following alkylator therapy.
Myelodysplasia and AML with losses or deletions in all or
parts of chromosomes 5 and/or 7 have been detected following
autologous bone marrow transplantation for various cancers, including lymphomas (14). Although alkylating agents are one
mainstay of myeloablative regimens, the hematopoietic stem
cell damage that causes these cases may occur during the
cytotoxic therapies given prior to bone marrow harvest and
myeloablation, rather than as a consequence of the bone marrow
transplantation preparative regimens (15).
Chromosome 5 encodes a number of key genes that direct
hematopoiesis and that may play a role in leukemia initiation
and progression and in full leukemia transformation (16-18).
This entire gene segment may be intrinsically unstable (16,17)
and is lost to varying extents in de novo AML as well as in environmentally induced and alkylator-induced AML (3,4,6,8,16).
The 5q31 -33 region of the long arm of the chromosome contains
at least nine genes that influence hematopoietic cell growth and
differentiation (e.g., granulocyte-macrophage colony-stimulating factor [GMCSF] and interleukins 3, 4, 5, and 9). Aberrant
expression of these growth factors could play a role in the
promotion or progression of a transformed clone. Other interesting genes in the 5q31-33 region include the interferon regulatory
factor 1 (IRF1) gene and the early growth response 1 (EGR1)
gene, both of which are deleted in some cases of myelodysplasia
and certain AML cases (17,18). IRF1 is a transcriptional activator of the interferon genes, and EGR1 is a zinc-finger protein
that is required for differentiation along the monocyte-macrophage lineage. EGR1 is the only gene found to be consistently
deleted in both de novo and secondary AML cases that have
chromosome 5 deletions (17). Other genes at 5q31-33 include
the FMS oncogene (encoding the receptor for macrophage
colony-stimulating factor 1, or CSF1) and the CDC25C gene
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Table 1. Clinical characteristics of secondary AMLs
DNA-damaging agents
Latency, y
Presentation
Genotype
4-6 y (range, l-20y)
Antecedent myelodysplastic
syndrome
Losses, deletions (-5,-7)
Phenotype
M6 and M7 (with myelofibrosis)
Topoisomerasedirected agents
1-3 y (range, 0.5-4.5 y)
Abrupt, no prodrome
Translocations [1 Iq23based;t(8;21);t(15;17)]
Monocytic (M4 and M5)
(encoding a phosphatase that activates the cyclin-dependent
kinase, CDC2).
While the majority of patients with 5q deletions exhibit losses
at the 5q31 locus, a small subgroup of patients (in particular
those with refractory anemia) exhibits deletion of 5q33 sequences without accompanying 5q31 gene losses (16). Furthermore,
no consistent mutations have been detected in the many candidate genes located on 5q31-33 in preleukemia or leukemia
(16,17); however, the deletion of one or more of these genes in
itself may be sufficient to induce cancer. Such an important role
for gene dosage has been demonstrated (or hypothesized) for a
number of genetic diseases, in which deletion of critical genes
creating a "haploinsufficient" state appears to be sufficient to
result in a clinical syndrome (e.g., aniridia [PAX6], Greig's
syndrome [GLI3], and the CATCH-22 syndrome [TUPLE1])
(19-22). "Haploinsufficiency" for critical genes involved in
hematopoiesis could disrupt the balance between growth and
differentiation leading to dysmyelopoiesis and "differentiation
arrest."
Topoisomerase-Associated Secondary AML
The DNA-intercalating anthracyclines and the topoisomerase
II (topo-II)-directed epipodophyllotoxins (e.g., etoposide and
teniposide) entered the oncologists' therapeutic armamentarium
in the 1970s and 1980s, respectively. In the late 1980s, a new
form of therapy-related AML associated with prior epipodophyllotoxin therapy was recognized (23-25). In contrast to
alkylating agent-associated secondary AML, epipodophyllotoxin-associated secondary AML exhibits a shorter latent
period (median of 24-30 months), monocytic phenotypes
(French-American-British [FAB] M4 or M5 classification), and
an acute presentation with substantial blast counts (rather than
gradual pancytopenia and fibrosis) (Table 1) (826).
The epipodophyllotoxins cause DNA damage via the intranuclear enzyme topo-II and stabilize the DNA—topo-II
covalent linkage (2728). In addition to their other biochemical
activities, the anthracyclines inhibit topo-II in a similar manner
(29JO). Exposure of cells to topo-II-active agents increases the
frequency of illegitimate recombination events (57), a
physiologic activity that may be related to both the cytotoxicity
and the leukemogenicity of the topo-II inhibitors (26,32).
The leukemogenic translocations induced by the topo-II-active agents often involve the MLL gene (mixed-lineage or
myeloid—lymphoid leukemia; also known as ALL1 and HRX)
located at chromosome band 1 Iq23 (12J3-36). The MLL gene
is the human homologue of the Drosophila trithorax gene that
Journal of the National Cancer Institute, Vol. 88, No. 7, April 3, 1996
regulates embryonic differentiation in Drosophila and which appears to play a role in controlling differentiation in primitive
hematopoietic stem cells (72,35). At least 21 different translocations involving chromosome band Ilq23 have been identified,
suggesting that the MLL gene has numerous translocation
partners with which it can combine to produce fusion proteins
that cause marked growth dysregulation and leukemic transformation (36,37).
The molecular characteristics of MLL-associated acute
leukemias are germane to their pathogenesis, to their diagnosis,
and to a diversity of treatment issues (e.g., monitoring of minimal residual disease during therapy and novel treatments
directed against the leukemia-specific fusion messenger RNAs
and proteins). Molecular dissection of the breakpoints on Ilq23
is providing insight into the pathogenesis of topo-II-associated
secondary leukemias (8,10^8-40). Most of the breakpoints
occur in a 9-kilobase (kb) region of the genomic DNA that includes exons 5-11 of the MLL gene. This genomic region contains a number of interesting DNA sequences that could be
involved in illegitimate recombination. They include the following: Alu sequences, topo-II consensus-binding sequences,
matrix-associated regions, VDJ recombinase recognition sites,
and sequences with homology to the chi recombinatorial element in Escherichia coli (35,41-44). Identification of the DNA
sequences at the breakpoint sites (both in the MLL gene and in
its translocation partners) will suggest which nuclear enzymatic
activities are involved in the translocation events. Preliminary
data suggest that the breakpoint sites for secondary AML translocations occur in a different segment of the 9-kb breakpoint
region than those associated with de novo AML (Rowley J: personal communication). Should this observation be verified for a
larger number of cases, it will provide evidence for distinctive
pathogenetic mechanisms for the de novo and secondary AML
cases that have translocations involving the MLL gene.
portant to carefully monitor their propensity to contribute to the
development of secondary leukemias.
The molecular phenotype of the Ilq23-associated acute
leukemias is clearly linked to the pathogenesis and diagnosis of
these leukemias but may also be relevant to treatment issues.
For example, it may be possible to monitor response to antileukemia treatment by detection of minimal residual disease
using probes for the aberrant chromosome band Ilq23 region.
New approaches to treatment of these secondary AMLs are
needed, since current leukemia treatment strategies are rarely
successful at achieving long-term survival. Specific treatments
may be designed to exploit the unique molecular aberrations associated with leukemogenesis. One strategy under investigation
is the use of antisense constructs and ribozymes directed against
the fusion gene products encoded by chimeric genes. At least in
theory, these antisense constructs and ribozymes could target in
a highly selective way the leukemia-related fusion gene or gene
products. Newly developed models in the severe combined immunodeficiency (SCID) mouse that utilize engraftment of
human leukemia cells provide a preclinical model for testing
these and other novel treatment strategies against cells with
specific translocations (59,60).
DNA Damage and Repair: a Focal Point for
Leukemogenesis
The repair of DNA damage is critical to the maintenance of
genomic integrity. In order to maintain effective "genomic surveillance" of both endogenous replication errors and exogenously induced genetic lesions, there are at least three distinctive
repair mechanisms: 1) nucleotide excision repair, 2) base excision repair, and 3) DNA mismatch repair (61-64). Nucleotide
excision repair is capable of repairing the widest variety of induced DNA lesions, whereas base excision repair is critical for
correction of lesions induced by alkylation as well as by reactive
The dioxypiperazine derivatives (e.g., Razoxane, ICRF-187,
oxygen species (67). Newly highlighted in human disease, DNA
and bimolane) are another class of topo-II inhibitors that have
mismatch repair targets endogenous errors in DNA replication
been associated with secondary AML. The interaction of the
(62). Each pathway requires a distinct cascade of genes and
dioxypiperazines with the topo-II enzyme results in inhibition of
proteins that are recruited into action when specific types of
formation of DNA-topo-II complexes, rather than stabilization
DNA damage are "sensed" (Table 2). Given the involvement of
of DNA-topo-II complexes (45-48). Members of this family of
exogenous mutagens in the pathogenesis of secondary
agents have been used to treat psoriasis in the U.K. (Razoxane) leukemias, it is plausible that a defect in the nucleotide excision
and in China (bimolane). After prolonged daily treatment with repair pathway could play a contributory role. Whatever the
these agents to high cumulative doses, cases of AML have been specific mechanism(s) involved, the consequences of defective
observed (49-52). In those cases with informative cytogenetics, DNA repair are evinced on the genomic level by mutations and
t(8;21) and t(15;17) (associated with FAB M2 and M3 subtypes, aberrant recombination events that can lead to cell cycle dysrespectively) have been most commonly observed (49J3).
regulation, genomic instability, uncontrolled proliferation,
The camptothecins, another class of antitumor agents, target blockage of differentiation, and abrogation of apoptosis (with
the topoisomerase I (topo-I) enzyme (54 J5). Like topo-II, topo- net drug resistance).
I forms a covalent linkage with DNA and is involved in DNA
A number of familial syndromes are associated with defective
replication and recombination. The camptothecins (e.g., topo- DNA repair and/or DNA damage hypersensitivity and include
tecan, irinotecan, and 9-aminocamptothecin) stabilize the DNA- ataxia-telangiectasia (AT), Bloom syndrome, Fanconi's anemia,
topo-I covalent complex, causing cytotoxic events when a DNA xeroderma pigmentosum (XP), and Cockayne's syndrome (CS).
replication fork meets a DNA-topo-I complex (56). Like topo-II These genetic conditions have allowed identification of critical
inhibitors such as etoposide, topo-I inhibitors induce sister components of the various DNA repair pathways (Table 2).
chromatid exchanges and are mutagenic, primarily by induction Studies of XP, a disorder characterized by the inability to excise
of gene deletions and rearrangements (57J>8). As the topo-I-ac- UV radiation-induced DNA damage, have been especially valutive agents are more widely used in clinical trials, it will be im- able in elucidating individual components of nucleotide excision
Journal of the National Cancer Institute, Vol. 88, No. 7, April 3, 1996
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409
Table 2. Selected mechanisms of repair of DNA damage
Repair mechanism
DNA mismatched repair
Nucleotide excision repair
Selected familial defects and
cancer-prone syndrome
Involved genes
Hereditary nonpolyposis colorectal cancer
Xeroderma pigmentosum (XP)
Cockayne's syndrome (CS)
Ataxia-telangiectasia (AT)
Li-Fraumeni syndrome?
MSH2, MLH1, PMS1, PMS2
XP complementation groups A-G
CS complementation groups A-B
ATM gene (mutated in AT)
p53-related interactions
Inducing factors
Endogenous base-pair mismatches
Exogenous and endogenous DNA
damage (UV or y irradiation,
oxidative damage)
repair (65). XP is composed of multiple complementation
groups, each of which represents a defect in a specific component of the nucleotide excision repair process (66). The XPA
gene product, for instance, recognizes and complexes with the
UV radiation-damaged DNA (67,68). The XPG gene product is
a nuclease that makes an incision at a site 3' to the damaged
DNA (65,69), whereas the XPF product functions as part of the
DNA damage recognition complex and as a nuclease making an
incision in the damaged DNA strand 5' to the lesion (70). The
gene products for XP complementation groups XPB and XPD
have DNA helicase activity (71-73) and are components of the
transcription factor complex TFIIH (74).
The multicomponent nature of the TFIIH complex may provide a molecular basis for the observed coupling of transcription
and DNA repair (74,75). RNA polymerase, the enzyme involved in transcription, is a highly processive enzyme that
remains tightly bound to DNA at the site of a DNA lesion (e.g.,
a cyclobutane pyrimidine dimer) (76). In one model for the coupling of transcription and DNA repair, the RNA polymerase enzyme that is stalled at a DNA lesion undergoes a conformation
change that leads to recruitment of TFIIH and other factors required for nucleotide excision repair (74). Further support for
the role of the TFIIH complex in coupling transcription and
DNA repair comes from studies identifying the genes responsible for CS (a syndrome associated with defective strandspecific repair of transcriptionally active genes): The CSA and
CSB (ERCC6) gene products associate with subunits of TFIIH,
and CSB contains consensus helicase motifs (77-79).
The coupling of transcription and DNA repair may explain
the variability in DNA repair rates between expressed and unexpressed genes (80), between the transcribed and nontranscribed
strands of individual genes (81), and between specific gene segments within a single gene (52). The faster repair of lesions on
the transcribed strand compared with the nontranscribed strand
suggests that lesions on the nontranscribed strand may be
protected from the repair process, permitting them to persist and
become incorporated permanently .into the genome. It is
provocative that the characteristics of persisting mutations induced by certain carcinogens (e.g., polycyclic aromatic hydrocarbons [PAHs] from tobacco smoke and UV light) in the tumor
suppressor gene p53 suggest that the causal lesion occurred on
the nontranscribed strand of DNA (83-88).
The tumor suppressor gene p53 plays an integral role in the
repair of DNA damage induced by ionizing radiation and other
types of genotoxic stress (89-92). Given the role of p53 in the
cell's response to DNA damage, it is plausible that abnormal
p53 activity could result in reduced ability to repair DNA
damage (93-95), leading to genomic instability and increased
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susceptibility to leukemogenesis (91,94,96^7). In this light, the
role of p53 in the cellular response to DNA damage is summarized below.
The study of AT, an inherited multisystem disorder caused by
mutations in a recessive gene on chromosome bands llq22-23,
has helped to elucidate the critical role of p53 in the cell's
response to genomic damage (98). AT is characterized at both
the molecular and clinical levels by hypersensitivity to radiation-induced DNA damage (99). The AT gene (ATM) has been
identified (100) and shows sequence similarity to a family of
signal transduction mediators with homology to phosphatidylinositol 3-kinase (101,102) that control progression through
the G, phase of the cell cycle [tori and tor2 in yeast (103,104),
mTOR in rodents (105), and FRAP in humans (106)]. The ATM
gene also shows homology to the yeast rad3 gene product
(which has helicase activity, is required for the nucleotide excision DNA repair pathway, and has homology to human
ERCC2/XPD) (107-109). Available data support a model in
which specific types of DNA damage cause activation of the AT
gene product, leading to p53 induction, which causes transcriptional activation of specific growth-arrest-DNA-damage-inducible (GADD) gene products (98,110,111). With the
identification of the ATM gene, characterization of the individual steps in this pathway should be forthcoming.
One mechanism by which p53 induces G] arrest following
DNA damage is by transcriptional activation of the gene encoding a 21-kd cyclin-dependent protein kinase (CDK) inhibitor
known as p 2l W A F - | / C I P I (wild-type p53-activated fragment 1
and CDK-interacting protein 1) (112-114); p 2l WAF -" CIp - 1 binds
to multiple G) CDKs and blocks the activation of cyclin-CDK
complexes, thus limiting their ability to phosphorylate target
substrates, notably the retinoblastoma proteins (pRbs)
(112,115,116). In turn, the maintenance of pRb in the hypophosphorylated state impedes movement across the G)/S boundary.
p53 may play a more direct role in modulating DNA repair
than simply delaying progression through G, and allowing more
time for DNA repair to occur. One mechanism by which p53
may more directly affect DNA repair is by recognizing and
binding to damaged DNA and then subsequently interacting
with and modifying the activity of components of the nucleotide
excision repair pathway. Wild-type p53 is able to form stable
complexes with DNA lesions, including insertion-deletion mismatches and lesions induced by ionizing radiation (117,118).
The C-terminal domain of p53 that is involved in binding to
damaged DNA also binds to transcription-repair factors (XPB,
XPD, and CSB) involved in the nucleotide excision repair pathway (95,119). XPB is a component of the TFTIH transcription
factor (75) and has helicase activity (71,72). When DNA is
Journal of the National Cancer Institute, Vol. 88, No. 7, April 3, 1996
damaged, p53 interactions with XPB and other transcriptionrepair factors may stall transcription either at the initiation stage
or at the elongation stage, thereby modulating preferential repair
of DNA damage within actively transcribed genes {119).
p53 may also modulate the balance between DNA repair and
DNA replication through p2i W A F 1 / C I P I inhibition of proliferating cell nuclear antigen (PCNA). PCNA is an essential DNA
replication protein and both facilitates loading of polymerase d
(in cooperation with replication factor C) and acts as a processivity factor for DNA polymerase d {120-122). The p 21 WAF -" CIp - 1
directly binds to PCNA and inhibits DNA replication catalyzed
by the DNA polymerases d and e {123-125). Thus, p 2l WAIi " CIp - 1
that is induced by p53 following DNA damage not only inhibits
cell cycle progression through its interactions with CDKs, but
also directly inhibits DNA synthesis by binding to PCNA. However, inhibition of PCNA following DNA damage could be
problematic, since PCNA also plays a pivotal role in nucleotide
excision repair {126-128), and inhibition of DNA repair following DNA damage would be counterproductive. The answer to
this apparent paradox is that p21WAFI/cu>"'-mediated inhibition
of PCNA differentially blocks synthesis of long (i.e., kilobase)
DNA fragments but not short (e.g., 10-base) DNA fragments
{124,125) and that PCNA-dependent nucleotide excision repair
is not blocked by p 2 1 W A F 1 / C I P 1 {124).
Another mechanism by which p53 may affect the balance between DNA replication and repair is via interactions between
p53-induced GADD45 and PCNA. Following a genotoxic
stress, p53 functions as a transcription factor to transactivate
GADD45 {98,129). GADD45 causes growth suppression {130)
and suppresses entry into S phase when it is overexpressed
(757). At the molecular level, GADD45 associates with PCNA
and stimulates PCNA-mediated nucleotide excision repair
(757). The combined effect of the p53-induced p 2 1 W A F " a p - '
and GADD45 following a genotoxic injury is inhibition of entry
into the S phase (through inhibition of CDKs), slowing of ongoing DNA replication (through interactions with PCNA), and
stimulation of DNA repair. Thus, p53 plays an important role in
the cell's response to DNA damage, and alterations in p53 function can lead to genomic instability and to an increased risk of
neoplastic transformation {91£4£6£7).
Studies in the BALB/c mouse plasmacytoma model provide
additional data supporting a coupling of tumorigenesis and
DNA repair efficiency. Following UV radiation-induced DNA
damage in splenic B lymphoblasts, the nucleotide excision
repair of the c-myc 5' and regulatory regions (but not the repair
of the 3' flank of c-myc or of dihydrofolate reductase gene segments) proceeds at a markedly higher rate in cells from mice
resistant to plasmacytoma development than in cells from mice
susceptible to plasmacytoma development {82). The 5' and
regulatory regions of c-myc are the major sites of chromosomal
breaks and translocations in B-cell lymphomas and leukemias
bearing c-myc translocations and rearrangements. The mouse
plasmacytoma system validates the notion that alterations in
DNA repair efficiency, especially the differential repair of gene
segments involved in recombination or transcriptional regulation, may contribute to neoplasia.
Journal of the National Cancer Institute, Vol. 88, No. 7, April 3, 1996
Molecular Epidemiology: Foundation for Clinically
Relevant Risk Prediction and Quantitation
The discipline of molecular epidemiology incorporates a
number of interdependent components that, when analyzed singly or in combination, may allow prediction of an individual's
risk for tumorigenesis following exposure to a potential tumor
initiator or tumor promoter {132,133). Molecular genetic and
biochemical processes that contribute to the leukemogenic susceptibility of an individual may be numerous, ranging from the
efficiency of DNA repair processes to polymorphisms in the
metabolism of mutagenic agents (such as chemotherapy).
One initial step in identifying a susceptible population is to
identify whether there is heterogeneity within the population in
the mutagenic burden incurred following cancer treatments.
Two tests that have been applied to measuring somatic cell
genetic damage following cancer therapy are the HPRT mutant
frequency assay and the glycophorin A somatic mutation assay
{134-137). For both tests, increases in mutant frequency are observed in cancer patients following treatment with cytotoxic
agents {138-144). One factor that has been associated with increased mutant frequency following cytotoxic therapy is serum
folate {145). Among a small series of breast cancer patients receiving diverse chemotherapy regimens that included cyclophosphamide, higher mutant frequencies were observed among
patients with lower pretreatment serum folate levels than among
patients with higher levels. It will be of interest to attempt to
identify additional patient factors associated with higher mutation frequencies following cytotoxic therapy.
The HPRT mutation assay has an advantage over the glycophorin A assay in that it can be performed on all patients and
does not depend on heterozygosity for measurement. In addition, use of the HPRT assay allows identification of specific
molecular changes resulting from the mutagenic challenge
{134,135,146). The HPRT mutation assay and molecular genetic
analysis of mutant clones have demonstrated that spontaneously
occurring mutations are most often point mutations {134), that
ionizing radiation tends to cause large deletions {146,147), and
that mutations occurring in infants typically involve translocations at VDJ recombinase recognition sites {148).
An important question is whether the HPRT gene can serve as
a surrogate marker for susceptibility to secondary AML, even
though the target cell of the assay (i.e., a lymphocyte) is different from the target cell for leukemogenesis (an early
hematopoietic cell). This question can be tested only if populations with higher mutation frequencies following cytotoxic
therapy can be identified and if the risk of secondary AML in
these patients can be reliably compared with the risk of secondary AML in patients with lower mutation frequencies. If indeed HPRT (or perhaps another gene) is a reliable surrogate
marker, then hypersensitivity to mutagen exposure may be useful as a biomarker of genetic susceptibility for leukemogenesis,
in much the same way as microsatellite instability linked to a
defect in DNA mismatch repair or chromosomal fragility in AT
can be used to identify populations at risk for certain cancers
{149).
Accepting that variations in mutagenic burden following
treatment with cytotoxic agents likely exist, then it becomes imREVIEW 411
portant to identify pathogenetic mechanisms for the variation in
mutagenic burden. A reasonable hypothesis is that higher levels
of carcinogen activation (or lower levels of carcinogen detoxification) lead to higher levels of DNA adduct formation,
higher levels of persistent mutations, and increased risk of cancer development following exposure to environmental carcinogens (or to increased risk of leukemia following exposure to
cancer therapies). Numerous examples from the genetic epidemiology literature suggest that this is the case, and several examples are briefly described.
The glutathione 5-transferases (GSTs) are a supergene family
capable of detoxifying a number of carcinogenic electrophiles
by catalyzing their conjugation to glutathione (750). For example, PAHs are detoxified by conjugation with glutathione,
preventing the formation of PAH-DNA adducts (757). Two of
the members of this class, glutathione S-transferase Ml
(GSTMl) and glutathione S-transferase theta (GSTT1), are
homozygously absent (the null phenotype) in a significant percentage of the population (approximately 50% for GSTMl and
20% for GSTT1) (152,153). As would be predicted by the role
of GSTMl in carcinogen detoxification, persons with the null
phenotype for GSTMl show higher levels of cytogenetic
damage (e.g., as measured by sister chromatid exchange) (154),
higher levels of PAH-DNA adducts (755,756), and higher
levels of mutagenic activity in their urine (757) than do persons
with the GSTMl gene present. Molecular epidemiologic studies
suggest that persons with GSTMl deficiency may have modest
increases in susceptibility to certain cancers, including some
types of lung cancer (158-163), bladder cancer (164-168), colon
cancer (769), melanoma (770), and malignant gliomas (171,172).
Of relevance to secondary AML etiology, a preliminary report
(775) noted elevated frequencies for both GSTMl and GSTT1
null genotypes among patients with myelodysplastic syndrome.
This observation requires confirmation in larger epidemiologic
studies.
Genetic variations in cytochrome P450 enzymes, another
class of enzymes involved in carcinogen metabolism, have been
associated with increased risk of certain cancers (132,174). The
cytochrome P450 enzymes are involved in metabolic activation
of precarcinogens to reactive metabolites, as well as in the
detoxification of natural products. Thus, a plausible hypothesis
is that individuals with higher levels of carcinogen-activating
enzymes will have higher levels of DNA adduct formation (156)
and higher risks of subsequent cancer development, whereas individuals with lower levels will be relatively protected from
cancer risks (132).
One member of the CYP-450 family, aromatic hydrocarbon
hydroxylase (AHH), is encoded by the CYP1 Al gene and is induced in the presence of PAHs. Alleles of the CYP1A1 gene
have been identified that have higher levels of activity and
higher levels of inducibility than the wild-type form (174,175).
Smokers with a genetic polymorphism of CYP1A1 that is associated with higher AHH activity have higher levels of DNAPAH adducts than smokers lacking this allele (176). In a
molecular epidemiologic study (177) of a Japanese population,
persons homozygous for the higher activity allele appeared to be
at increased risk of developing lung cancer (174,177), although
412
REVIEW
this association has not been observed in most studies of nonOriental populations (178-181).
Another member of the CYP-450 family showing genetic
polymorphism is CYP2D6. Tobacco smoke nitrosoamines can
be activated by CYP2D6 (182,183), and individuals with
genotypes consistent with higher levels of CYP2D6 activity
were found to have higher levels of 7-methyl-deoxyguanosine
monophosphate (a DNA adduct associated with tobacco-specific
nitrosoamines) than individuals with genotypes predictive of
low CYP2D6 activity (156). The CYP2D6 enzyme has traditionally been assayed by measuring the extent of metabolism of
debrisoquine (an antihypertensive medication), and genetic
polymorphisms have been identified that are predictive of the
debrisoquine metabolizer phenotype (184,185). Approximately
90%-95% of the population are classified as extensive metabolizers of debrisoquine, and these persons are reported in some
studies to be at increased risk of developing lung cancer in comparison to the 5%-10% of the population who are poor metabolizers (186-189). Other studies, however, have not found
increased risk of lung cancer for the extensive debrisoquine metabolizer phenotype (790) or for genotypes associated with extensive metabolism (797), illustrating how difficult it can be to
define and understand the contributions of genetic susceptibility
to cancer risk (192). An increased risk of liver cancer has also
been reported for persons who are homozygous for functional
CYP2D6 genes, compared with persons with fewer than two
functional CYP2D6 genes (795).
Studies evaluating both CYP1A1 and GSTMl polymorphisms (161,174,177,194) illustrate another important concept,
that persons with high levels of carcinogen-activating enzyme
activity (e.g., alleles of CYP1 Al with higher activity) and low
levels of detoxifying enzyme activity (e.g., the GSTMl null
genotype) may be at higher risk of developing specific types of
cancers. In a similar manner, persons with high levels of two
carcinogen-activating enzymes that are in the same metabolic
pathway would be predicted to be at increased risk of developing cancer. Such a relationship is suggested for colon cancer in
which heterocyclic aromatic amines activated by yV-acetyltransferase 2 (NAT2) and CYP1A2 are thought to play an
etiologic role (795): Individuals who are both rapid acetylators
(mediated by NAT2) and rapid A'-oxidizers (mediated by
CYP1A2) of heterocyclic amines appear to be overrepresented
among colon cancer cases (196,197).
Another method that may be useful in identifying cancer
patients who may be at risk for subsequently developing secondary AML is identification and quantitation of known leukemogenic translocations in hematopoietic cells following chemotherapy. It is technically feasible to use polymerase chain reaction assays to detect translocations involving the MLL gene in
peripheral blood or bone marrow cells (detection limit of approximately one abnormal cell among ^ n o r m a l cells). Evaluations of large numbers of patients treated with topo-II-active
agents will be necessary to define a relationship between the
level of MLL translocation events during and after chemotherapy and subsequent risk of developing AML. If a relationship can be demonstrated, then detection of these molecular
lesions could identify individuals at particular risk for leukemogenesis from topo-II-active agents, and alternative chemoJournal of the National Cancer Institute, Vol. 88, No. 7, April 3, 1996
therapy agents could be considered for these patients. It may
also be feasible to use in vitro assays to evaluate the sensitivity
of normal hematopoietic precursors to induced DNA damage at
the critical 1 Iq23 gene loci.
Longitudinal Monitoring of High-Risk
Populations
Concerns about secondary AML were heightened recently
with the detection of six cases of AML arising in the National
Surgical Adjuvant Breast and Bowel Project B-25 trial among
approximately 2550 women treated for stage II breast cancer
with one of three dose schedules of adjuvant therapy combining
cyclophosphamide, doxorubicin, granulocyte colony-stimulating
factor, and tamoxifen (for postmenopausal women) (198). The
leukemias occurred in women aged 50-69 years at 10-18 months
after they began adjuvant therapy. All of the AML case subjects
had either FAB M4 or FAB M5 morphology, and two of the
case subjects on whom cytogenetic analysis was performed had
1 Iq23 abnormalities.
Available data from large cooperative group clinical trials
suggest that secondary AML occurring so quickly after the initiation of therapy is unusual for adjuvant therapy using doxorubicin and cyclophosphamide at standard doses. Thus, concerns
were raised that the dose-intensive use of cyclophosphamide in
combination with doxorubicin may increase the risk of secondary AML. To address these concerns, the Cancer Therapy
Evaluation Program (CTEP) of the NCI has established a
monitoring plan to quantitate the risk of secondary AML following dose-intensive treatment strategies. The monitoring plan to
accomplish this objective builds upon the CTEP/NCI experience
with the epipodophyllotoxin-monitoring plan (199). The underlying assumption of the epipodophyllotoxin-monitoring plan is
that estimates of risk can be obtained most quickly and reliably
by pooling data from multiple protocols that all administer
epipodophyllotoxins using similar schedules and cumulative
doses. The CTEP/NCI plan provides for complete ascertainment
of secondary AML/myelodysplastic syndrome cases by using
existing cooperative group mechanisms for patient follow-up
and for reporting serious adverse events. The plan identifies the
target population prospectively (on the basis of their entry into
the protocols of the monitoring plan), so that both secondary
AML/myelodysplastic syndrome cases and total patient-years of
follow-up for the entire patient population could be accurately
determined. In a similar manner, NCI cooperative group
protocols that prescribed similar doses and dose intensities of
alkylators and anthracyclines were grouped together so that the
following questions could be addressed:
1) What is the risk of developing secondary AML/myelodysplastic syndrome following treatment with doxorubicin and
cyclophosphamide (AC therapy) at standard dose intensity?
2) Is the risk of developing secondary AML/myelodysplastic
syndrome increased following intensive AC therapy that uses a
higher dose intensity of cyclophosphamide but a total cumulative dose of cyclophosphamide similar to that of standard AC
therapy?
3) Is the risk of developing secondary AML/myelodysplastic
syndrome increased following intensive AC therapy that uses a
Journal of the National Cancer Institute, Vol. 88, No. 7, April 3, 1996
higher dose intensity of cyclophosphamide, along with a higher
cumulative dose of cyclophosphamide (compared with standard
AC therapy)?
4) Is the risk of developing secondary AML/myelodysplastic
syndrome increased following therapy with cyclophosphamideanthracycline combinations, when only the anthracycline is
given at a higher dose intensity?
5) Does the use of granulocyte colony-stimulating factor affect the incidence of secondary AML/myelodysplastic syndrome
following chemotherapy?
6) Does the use of tamoxifen affect the incidence of secondary AML/myelodysplastic syndrome following chemotherapy?
The clinical cooperative groups are also well positioned to
evaluate factors that may predispose to the emergence and perpetuation of secondary AML. For example, the evaluation of
biologic factors (acquired or genetic) that may predispose individuals to the development of secondary AML following
therapy for cancer will require studying large cohorts of patients
at multiple time points (e.g., before, during, and after completion of their primary cancer therapy). As described above,
potential biologic factors for study include deficiencies in DNA
repair pathways and abnormalities or polymorphisms that affect
metabolic pathways for specific chemotherapy agents. Whatever
the questions, the answers will evolve only with careful
laboratory investigations that are linked to the clinical setting.
Such studies mandate the need for carefully designed clinical
trials that include (and perhaps intentionally recruit) patients
with secondary AML.
Future Directions
The secondary leukemias are an ironic and tragic consequence of progress in the treatment of other cancers and are
likely to increase as success with cytotoxic therapies for solid
tumors and for other hematologic cancers also increases. As outlined in Table 3, molecular studies of the "induced" leukemias
will inform issues surrounding genomic instability and the
emergence of particular genomic lesions as a consequence of
specific toxin-DNA interactions. Longitudinal studies that
quantitate dose-risk relationships for leukemogenic agents
should provide an ability to define individual risk for leukemia
induced by a particular toxin. Serial monitoring of individuals at
risk for the earliest genetic changes could lead to intervention
before cumulative genetic damage and irreversible transformation ensue. And finally, for those individuals who are defined as
being susceptible to the leukemogenic effects of a drug, it may
be possible to avoid the offending agent altogether (if alternative
options exist). In this regard, the study of therapy-related AML
Table 3. Selected key areas of investigation of secondary leukemias
Dissect the structure and function of induced genetic lesions as a basis for innovative therapeutic interventions.
Identify and characterize mechanisms of DNA damage and repair.
Develop and apply accurate biomarkers of leukemogenesis for the purpose of
risk prediction and quantification and as the first step toward prevention.
Design and implement longitudinal clinical and genetic monitoring of highrisk populations.
REVIEW
413
provides an excellent template for all environmental-occupational cancers with respect to dissecting the molecular epidemiology, quantitating individual risk, and characterizing
formative "premalignant" genetic changes as a molecular foundation for developing, implementing, and measuring clinical
prevention interventions. Given their present resistance to current therapeutic strategies, these challenging leukemias also provide an important testing ground for mechanistically novel
approaches. Ultimately, all of these studies will inform our understanding of so-called "de novo" leukemia and serve as a
springboard for the development of new concepts of therapy and
prevention.
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Notes
Participants at the National Cancer Institute (NCI>Leukemia Society of
America (LSA) Workshop on Secondary Leukemias: J. Abrams (NCI, Bethesda,
MD), J. Ajani (The University of Texas M. D. Anderson Cancer Center, Houston), R. Albertini (University of Vermont, Burlington), M. Amylon (Stanford
University Medical Center, CA), P. Apian (Roswell Park Cancer Institute, Buffalo, NY), D. Bell (National Institute of Environmental Health Sciences, Research Triangle Park, NC), W. Bigbee (University of Pittsburgh, PA), C.
Bloomfield (Roswell Park Cancer Institute), V. Bohr (National Institute on
Aging, Baltimore, MD), J. Boice (NCI), M. Bookman (Fox Chase Cancer Center, Philadelphia, PA), N. Breslow (University of Washington, Seattle), P. Burke
(Johns Hopkins Oncology Center, Baltimore), M. Caligiuri (Roswell Park Cancer Institute), B. Cheson (NCI), R. Curtis (NCT), A. DeCillis (National Surgical
Adjuvant Breast and Bowel Project, Pittsburgh), J. Deeg (Fred Hutchinson Cancer Center, Seattle, WA), P. Domer (Northwestern University, Chicago, IL), M.
Doukas (VA Medical Center, Lexington, KY), M. Evans (National Institute on
Aging), C. Felix (Children's Hospital of Philadelphia), J. Finerty (NCI), S. Forman (City of Hope Medical Center, Duarte, CA), A. Fornace (NCI), M. Friedman (Food and Drug Administration, Rockville, MD), R. Geller (Emory
University, Atlanta, GA), R. Gelman (Dana-Farber Cancer Institute, Boston,
MA), H. Gill-Super (University of Chicago), S. Gore (Johns Hopkins Hospital,
Baltimore), B. Grant (University of Vermont), M. Grever (Johns Hopkins Oncology Center), K. Hays (University of Pittsburgh), P. Ho (NCI), J- Jacobson
(NCI), J. Karp (NCI), S. Kaufmann (Mayo Clinic, Rochester, MN), P. Keegan
(Food and Drug Administration), B. Kimes (NCI), I. Kirsch (NCI), V. Land
(Pediatric Oncology Group, Chicago), R. Larson (University of Chicago Medical Center), M. LeBeau (University of Chicago), R. Lemons (Primary Children's
Medical Center, Salt Lake City, UT), E. Levine (Roswell Park Cancer Institute),
M. Litzow (Mayo Clinic), R. McCaffrey (Boston University Medical Center), K.
McCarty (University of Pittsburgh), K. Miller (New York University School of
Medicine), S. Mitra (University of Texas Medical Branch—Galveston), S. Murphy (Children's Memorial Hospital, Chicago), E. Paietta (Montefiore Hospital
and Medical Center, New York, NY), J. Pederson-Bjergaard (Rigshospitalet,
Copenhagen, Denmark), Y. Pommier (NCI), J. Radich (University of Texas, San
Antonio), B. Raney (The University of Texas M. D. Anderson Cancer Center),
P. Ravdin (University of Texas Health Science Center, San Antonio), R. Rednor
(University of Pittsburgh), E. Reed (NCI), M. Relling (St. Jude Children's Research Hospital, Memphis, TN), J. Rowe (University of Rochester Medical Center, NY), J. Rowley (University of Chicago Medical Center), E. Sausville (NCI),
P. Schulman (North Shore University Hospital, Manhasset, NY), K. Shannon
(University of California, San Francisco), D. Shrimer (NCI), M. Smith (NCI), J.
Sogn (NCI), W. Stock (Loyola University Medical Center, Chicago), M.
Tallman (Northwestern University), P. Therasse (European Organization for Research and Treatment of Cancer, Brussels, Belgium), L. Travis (NCI), W.
Velasquez (St. Louis University Medical Center, MO), G. Verdine (Harvard
University, Cambridge, MA), R. Wu (NCI), and C.-H. Yang (NCI).
The Secondary Leukemia Workshop was supported by the NCI and the LSA.
We gratefully acknowledge the thoughtful review of the manuscript and comments provided by Drs. Janet Rowley, Michele Evans, Douglas Bell, and
Richard Albertini. We thank Dr. Rowley for communicating data prior to publication.
Manuscript received August 2, 1995; revised October 30, 1995; accepted
December 14, 1995.
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Journal of the National Cancer Institute, Vol. 88, No. 7, April 3,1996