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Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-08-2394.
NEOPLASIA
From the Department of Genetics and the MRC Toxicology
Unit, University of Leicester; and the Medical Research Council
Radiation and Genome Stability Unit, Chilton, Didcot, Oxon,
United Kingdom.
Inbred CBA/H mice are susceptible to radiation-induced
acute myeloid leukemia (r-AML), and C57BL/6 mice are resistant. A
genome-wide screen for linkage between genotype and phenotype
(r-AML) of 67 affected (CBA/H × C57BL/6)F1 × CBA/H
backcross mice has revealed at least 2 suggestive loci that contribute
to the overall lifetime risk for r-AML. Neither is necessary or
sufficient for r-AML, but relative risk is the net effect of
susceptibility (distal chromosome 1) and resistance (chromosome 6)
loci. An excess of chromosome 6 aberrations in mouse r-AML and bone
marrow cells up to 6 months after irradiation in vivo suggests the
locus confers a proliferative advantage during the leukemogenic
process. The stem cell frequency regulator 1 (Scfr1) locus
maps to distal chromosome 1 and determines the frequency of hemopoietic
stem cells (HSCs) in inbred mice, suggesting that target size may be
one factor in determining the relative susceptibility of inbred mice to
r-AML.
(Blood. 2003;101:2349-2354) Cancer is the result of the accumulation of genetic
lesions (mutations) in a single cell over time. The lifetime relative risk for cancer therefore increases with age and is determined by the
mutation rate, the number of genetic lesions required for malignant
transformation, the number of target cells, and intercurrent mortality.
Exposure to a carcinogen or the inactivation of gene(s) involved in
maintaining genetic stability increases the mutation rate and the
probability of malignant transformation. There is also a genetic
component that determines relative susceptibility to de novo or induced
cancer, and though this is exemplified in the germline transmission of
rare, highly penetrant alleles in familial cancer predisposition
syndromes, there is increasing evidence that a high proportion of
cancers arise in a susceptible subpopulation that carries
low-penetrance gene(s).1-3
Studies of Japanese atomic bomb survivors and of radiotherapy and
chemotherapy patients have shown that the main long-term health
consequence of exposure is acute myeloid leukemia (AML) and
myelodysplasia (MDS). Radiation- and therapy-related acute myeloid
leukemias (r-AML and t-AML) are clonal malignancies that arise in most
cases from a multipotent hemopoietic stem cell (HSC) and commonly
exhibit allelic loss (5q r-AML in inbred CBA/H mice is widely considered the most appropriate
mouse model of human r-AML. Mouse r-AMLs arise after a long latency
(mean latency, 480 days after irradiation), indicating that malignant
transformation of the target HSC is a multistage process and there is a
low (less than 0.1%) incidence of de novo AML in control CBA/H
mice.16,17 A curvilinear radiation dose-response curve in
mice and humans is composed of an initial increase in AML risk
according to (dose),2 followed by a decrease at
higher doses,6,16 and is presumably the net result of 2 opposing dose-dependent processes The differences in susceptibility to r-AML in the CBA/H and C57BL/6
inbred mouse strains can be exploited in genetic linkage analyses to
map r-AML susceptibility or resistance loci as the first step in the
identification of the gene(s) involved. The lifetime incidence of r-AML
in 3 Gy X-irradiated CBA/H mice is approximately 20%, but the
incidence of r-AML in 3 Gy X-irradiated (CBA/H × C57BL/6)F1
and F1 backcross and F1 intercross mice is approximately
7%.16,17 r-AML susceptibility is a complex polygenic and
partially dominant mouse genetic trait, and the risk following exposure is dependent on genetic background. We have therefore carried
out a genome-wide screen for linkage between phenotype (r-AML) and
genotype in affected and unaffected 3 Gy X-irradiated (CBA/H × C57BL/6)F1 × CBA/H backcross mice and identified at least 2 suggestive loci on chromosomes 1 and 6. Compared with the (CBA/H × C57BL/6)F1 × CBA/H backcross cohort as a whole, the loci
individually increase the relative risk for r-AML by approximately
2-fold, suggesting that r-AML susceptibility in mice is determined by at least 2 low-penetrance genetic loci in the inbred mouse genetic backgrounds used in this study.
Because the long-term repopulating HSC (LT-HSC) is the target cell in
radiation-leukemogenesis, the susceptibility/resistance gene(s)
products must either have a role in the regulation of LT-HSCs or their
response to ionizing radiation, or they must confer a proliferative
advantage during the radiation leukemogenic process. An excess of
chromosome 6 aberrations in r-AMLs and irradiated bone marrow cells
implicates the locus in preleukemic cell proliferation. The stem cell
frequency regulator 1 (Scfr1) locus maps to the r-AML-susceptibility locus on distal chromosome 1, so genetically determined target size (LT-HSC numbers) may be one factor in the susceptibility to induced AML.
Mouse irradiations
Moribund mice were killed by cervical dislocation. Blood and bone
marrow smears were taken for microscopic analyses, and tails, leukemic
spleens, and kidneys were snap frozen. DNA was prepared from control
(tail, kidney, or both) and leukemic spleen essentially as
described.17,19
Leukemia diagnosis
Genome-wide screen for linkage Microsatellite primer sequences were from the Whitehead Institute,20 and genetic positions were from the 2000 Chromosome Committee Reports (Jackson Laboratory21). Five hundred eighty-seven microsatellite markers across the 19 mouse autosomes were screened for informative polymorphisms in the inbred CBA/H and C57BL/6 mice. One hundred thirty-eight were identified to give a genome-wide screen at approximately 20-centimorgan (cM) intervals. Statistical significance of excess heterozygosity or homozygosity at individual microsatellite markers in the affected mice was evaluated using the 2
test for homogeneity and was compared with unaffected mice using the
2 test of independence.22 Relative risk
(RR) was estimated essentially as described.23
Leukemia incidence in backcross mice The lifetime incidence of r-AML in 3 Gy X-irradiated CBA/H mice is approximately 20%, whereas it is undetectable in X-irradiated C57BL/6 mice.16-18 We have previously shown that there is no statistically significant difference (P = .3) in the proportions of mice with r-AML in irradiated (CBA/H × C57BL/6)F1, F1 backcross, and F1 intercross mice (approximately 7% lifetime incidence), but they all differ significantly (P = .0000013) from the r-AML incidence in the parental CBA/H strain.17 To further elucidate the complex genetics underlying r-AML susceptibility in CBA/H mice, 1087 (CBA/H × C57BL/6)F1 × CBA/H mice (F1 × CBA/H) were exposed to 3 Gy x-rays, and causes of death were determined over their lifetimes. Sixty-seven r-AMLs were diagnosed.Genetic linkage analysis Fifty-eight to 67 affected mice were genotyped in a genome-wide screen of the 19 autosomes at intervals smaller than 22 cM using polymorphic chromosome-specific microsatellite markers (Table 1).
Sex chromosomes were not analyzed because susceptibility to r-AML is
not sex linked.17 In the first instance, excess
homozygosity or heterozygosity was estimated using the Two hundred eighty-eight to 357 mice of the 1020 irradiated F1 × CBA/H cohort that died of other causes (DOC) were also genotyped at the chromosomal intervals of interest to exclude segregation distortion and to test for the enrichment of specific genotypes in the affected mice using the
The excess homozygosity detected on chromosome 2 (D2Mit237) in the
affected mice was not significantly different than the D2Mit237
genotype of 272 unaffected mice (P = .28), so linkage to
proximal chromosome 2 is excluded (data not shown). Comparison of the
affected and unaffected mice using the Neither locus is essential for r-AML induction in the backcross mice.
For example, compared with the 67 affected F1 × CBA/H mice, the
RR of r-AML in the F1 × CBA/H mice that are homozygous at
D1Mit150 on chromosome 1 is 2.17 (P = .0072), and the RR
for excess heterozygosity on chromosome 6 is 2.75 (P = .00046). To determine whether each locus contributes
additively to r-AML risk, the 4 genotype combinations for the most
informative loci on chromosomes 1 (D1Mit150; 1hom or
1het) and 6 (D6Mit384; 6hom or
6het) were assessed in the affected mice and in 322 mice
that died of other causes. As illustrated in Table
3, the
During the course of these studies, 54 early pre-B mixed-lineage
lymphomyeloid leukemias (L-MLs) were
diagnosed19 in the irradiated backcross mice. The r-AML
and L-ML loss of heterozygosity profiles on chromosomes 2 and 4 differ,19 suggesting that they represent 2 distinct
hemopoietic malignancies, and mice affected with L-ML are included in
the unaffected mice that died of other causes (Tables 2-3). However,
further evidence to support the proposition that 2 distinct
leukemogenic processes are involved can be inferred when the 4 genotype
combinations for the most informative loci on chromosomes 1 (D1Mit150;
1hom or 1het) and 6 (D6Mit384; 6hom
or 6het) were compared in r-AML- and L-ML-affected mice.
As shown in Table 4, the
Because the lifetime incidence of r-AML in the F1 × CBA/H mice as a whole is 6.7% and the F1 × CBA/H subpopulation with the most favored 1hom6het genotype has a 2.99 RR, the incidence of r-AML in the hybrid 1hom6het genotype F1 × CBA/H mouse subpopulation is similar to the 20% lifetime r-AML incidence in the parental inbred CBA/H strain.16,17
The r-AML-susceptible CBA/H and resistant C57BL/6 inbred mouse strains have been exploited in a genome-wide genetic linkage analysis of (CBA/H × C57BL/6)F1 × CBA/H backcross mice to identify at least 2 suggestive loci (chromosomes 1 and 6), each of which makes a modest approximately 2-fold contribution to the RR of r-AML in the (CBA/H × C57BL/6)FI × CBA/H backcross mice following exposure to 3 Gy x-rays. Together, a RR of 3 for both genotypes accounts for the difference in the lifetime r-AML incidence in the irradiated F1 × CBA/H backcross cohort as a whole (6.7% incidence) and in the irradiated parental inbred CBA/H mouse strain (20% incidence). Although the results of the approximately 1500 cM genetic linkage
analysis has focused attention on 2 suggestive, approximately 7-cM
chromosomal intervals, it is self-evident that neither is necessary nor
sufficient for r-AML and that other low-penetrance genes are clearly
involved. The statistical power of the current study of (CBA/H × C57BL/6)F1 × CBA/H backcross mice is constrained by the low
(approximately 7%) lifetime incidence of r-AML in the 1037 X-irradiated mice analyzed. For example, there is weak evidence that
loci on chromosomes 4 and 13 may also be involved (Table 1), but the
statistical power is insufficient to satisfy the accepted criterion for
suggestive linkage.24 Nevertheless, the intervals on mouse
chromosomes 1, 6, and 13, defined by the minimum P values in
the Although each interval contains more than 100 genes, there must be a difference in the biologic activity of the susceptibility/resistance gene product(s) in the r-AML-susceptible and the r-AML-resistant mouse strains. Our current understanding of the radiation myeloid leukemogenic process suggests that the gene product(s) probably has a role in the regulation of the target LT-HSC, the cellular response to ionizing radiation and/or confer a proliferative advantage to the preleukemic LT-HSC. Furthermore, r-AML susceptibility/resistance loci do not appear to be involved in the leukemogenic process leading to mixed-lineage early to pre-B lymphomyeloid leukemia in the same irradiated backcross mice. The stem cell frequency 1 locus (Scfr1), which
determines the frequency of bone marrow long-term culture-initiating
cells (LTC-IC) in inbred mice, maps to the interval between D1Mit113 (90 cM) and D1Mit17 (113 cM),25 a significant overlap with
the 92.3 to 100 cM chromosome 1 interval defined by D1Mit111 and
D1Mit150, which have the minimum P values in the genetic
linkage analysis (Table 2). Because LTC-ICs are phenotypically and
functionally indistinguishable from LT-HSCs25 and are
therefore the target cell in r-AML, Scfr1 is an obvious
candidate. Independent studies have shown that adult C57BL/6 mice have
lower bone marrow LT-HSC numbers than other inbred mouse strains. For
example, AKR/J mice have 5 times more Lin The excess heterozygosity detected on chromosome 6 (Table 2) suggests the presence of a CBA/H r-AML resistance locus. However, loss of heterozygosity (LOH) studies did not detect allelic loss on chromosome 6 in r-AMLs34 (and data not shown), indicating that the locus does not appear to be subject to the inactivation processes normally associated with tumor-suppressor genes. More than 100 r-AMLs that arose in irradiated inbred CBA, C3H, RFM, and B6C3F1 genetic backgrounds have been analyzed for clonal chromosomal abnormalities by conventional G-banding or fluorescence in situ hybridization (FISH).35-39 As summarized in Table 1, allelic loss (terminal or interstitial deletions) on chromosome 2 is observed in more than 95% of r-AMLs, and aberrations on chromosome 6 represent the next most frequent clonal aberration (33.5%), followed by chromosome 15 (22%). Significantly, trisomy 6 (15%) is observed at a greater than 2-fold higher frequency than trisomy 15 (7.1%) or 1 (6%) and at a greater than 3.5-fold higher incidence than trisomy of any of the other 15 autosomes. Chromosomal abnormalities involving chromosome 15, and trisomy in particular, are frequently observed in mouse radiation-induced thymic lymphomas and have been implicated in tumor progression.40 In addition to the relative excess of chromosome 6 aberrations in the r-AMLs, an excess of CBA/H mouse bone marrow cells carrying aberrations of chromosomes 2 or 6 have also been reported in mice up to 6 months after exposure to 3 Gy x-rays,41 suggesting that these aberrations confer a proliferative advantage in vivo. This is consistent with the genetic analyses that indicate that though excess heterozygosity on chromosome 6 is neither necessary nor sufficient for radiation leukemogenesis, it does increase the RR of r-AML. Ionizing radiation induces genetic instability in the clonal descendants of a single irradiated cell that persists for many cell generations in vitro and in vivo, so exposure potentially results in an elevated mutation rate.42,43 Radiation-induced genetic instability is induced at a higher efficiency in the clonal descendants of irradiated short-term repopulating HSCs (ST-HSCs) from the r-AML-susceptible CBA/H mouse than in ST-HSC from the r-AML-resistant C57BL/6 mouse, and it appears to be a recessive CBA/H genetic trait because it is induced at the lower efficiency in the (CBA/H × C57BL/6)F1 hybrid.44 A modest increase in mutation rate caused by a genetically determined susceptibility to radiation-induced genetic instability could result in a modest increase in the risk for r-AML without its being absolutely necessary for the radiation-leukemogenic process. Significantly, a genetic component to radiation-induced genetic instability has also been observed in human ST-HSC45 and ongoing chromosomal instability detected in mouse and human r-AML.36,46 The genetic data presented here are further supportive17 evidence that r-AML susceptibility in the CBA/H mouse model is a complex polygenic trait involving low-penetrance resistance and susceptibility loci. Because this is consistent with the proposal that most cancers and leukemias arise in a susceptible human subpopulation,3 the CBA/H mouse model may be more relevant to human-induced AML than might have been expected. Furthermore, the colocalization of the suggestive chromosome 1 r-AML susceptibility locus and Scfr1 raises the possibility that in addition to the number of genetic lesions required for malignant transformation and the mutation rate, target cell numbers may be part of the equation defining target size in oncogenesis. This is a provocative but testable hypothesis, and it has potential implications in our understanding of low-penetrance genetic risk factors.
Submitted August 8, 2002; accepted October 21, 2002.
Prepublished online as Blood First Edition Paper, October 31, 2002; DOI 10.1182/blood-2002-08-2394.
Supported by the Medical Research Council and by the Leukaemia Research Fund. C.C. and H.C. were supported by MRC Research Studentships.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Mark Plumb, Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom; e-mail: map12{at}le.ac.uk.
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  M Jawad, G Giotopoulos, C Cole, and M Plumb Target cell frequency is a genetically determined risk factor in radiation leukaemogenesis Br. J. Radiol., September 1, 2007; 80(Special_Issue_1): S56 - S62. [Abstract] [Full Text] [PDF]
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 M. Jawad, C. H. Seedhouse, N. Russell, and M. Plumb Polymorphisms in human homeobox HLX1 and DNA repair RAD51 genes increase the risk of therapy-related acute myeloid leukemia Blood, December 1, 2006; 108(12): 3916 - 3918. [Abstract] [Full Text] [PDF]
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 F. Darakhshan, C. Badie, J. Moody, M. Coster, R. Finnon, P. Finnon, A.A. Edwards, M. Szluinska, C.J. Skidmore, K. Yoshida, et al. Evidence for complex multigenic inheritance of radiation AML susceptibility in mice revealed using a surrogate phenotypic assay Carcinogenesis, February 1, 2006; 27(2): 311 - 318. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
or monosomy 7), and 10% to 15% of newly
diagnosed cases of 5q
mutation induction and cell death.
In contrast, inbred C57BL/6 mice are susceptible to radiation-induced thymic lymphoma, a thymus-dependent T-cell malignancy that has no human
counterpart,
Thy-1low Sca-1+ c-kit+
bone marrow cells than C57BL/6 mice
-irradiated C57BL/6J mice.
Leukemia.
1988;2:115-119
-particle-induced chromosomal instability.
Int J Radiat Biol.
1997;71:497-503