The D5Mit7 locus on mouse chromosome 5 provides resistance to
-ray-induced but not N-methyl-N-nitrosourea-induced thymic lymphomas
Yasumitsu Kodama1,2,
Yoshihiro Yoshikai1,
Yasushi Tamura1,
Shigeharu Wakana4,
Ritsuo Takagi2,
Ohtsura Niwa5 and
Ryo Kominami1,3,6
1 Department of Molecular Genetics and 2 Department of Oral Health Science, Graduate School of Medical and Dental Sciences and 3 Center for Transdisciplinary Research, Niigata University, Asahimachi 1-757, Niigata 951-8122, 4 RIKEN Institute, Yokohama, Tozuka-Ku 244-0804 and 5 Radiation Biology center, Kyoto University, Yoshida-Konoecho, Sakyou-Ku 606-8315, Kyoto, Japan
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Abstract
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Susceptibility to
-ray induction of thymic lymphomas in mouse strains is controlled by low-penetrance genetic variant alleles. Our previous genome-wide scan of a mouse backcross between BALB/c and MSM strains suggested the existence of a BALB/c resistance locus near D5Mit5 on chromosome 5. To confirm this resistance, we produced congenic mice carrying a 28.4 cM region between D5Mit4 and D5Mit315 from the MSM parental strain on the BALB/c background. Lymphomas were induced in their progeny by
-ray irradiation or administration of N-methyl-N-nitrosourea (MNU), an alkylating agent. The incidence of radiogenic lymphomas was 87.5% in mice of the M/M genotype at D5Mit7, significantly higher than the 46% incidence in mice of the C/M genotype, indicating highly significant linkage between the locus and the resistance (P = 0.000054). In contrast, the frequencies of MNU-induced thymic lymphomas were similar between the two genotypes (P = 0.35 in
2 test). These results confirm the presence of a resistance allele for
-ray induction of thymic lymphomas near the D5Mit7 locus and strongly suggest that this locus modifies carcinogenic risk from exposure to radiation but not to alkylating agents.
Abbreviations: MNU, N-methyl-N-nitrosourea
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Introduction
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Genetic variation plays a key role in determining the range of individual susceptibility to cancers in human. Population-based epidemiological studies suggest that a high proportion of cancers arise in a susceptible subpopulation that carries low-penetrance variant alleles, indicating the importance of such variants (15). In contrast, many tumor suppressor genes have been shown to play a major role in development of human cancers (6), but the contribution of such genes including p53 and Apc to tumor susceptibility is noticed only in those rare families that transmit non-functional alleles through the germline (1,2). Thus, individual risks seen in the inherited cancer syndromes may be of much less significance to public health than predisposition by combinations of weak genetic variants.
The mapping and isolation of low-penetrance susceptibility genes in humans are complicated by the multiplicity of unlinked loci, which mask clear-cut familial clustering. On the other hand, mouse models of cancer susceptibility show that combinations of common alleles can exert a profound influence on tumor susceptibility, and experimental strategies for fine mapping of complex traits are well established in mouse models (7). For instance, a classic model of radiation-induced mouse thymic lymphomas (810) clearly exhibits the presence of low-penetrance susceptibility genes in mouse strains (1113). We carried out previously a genome-wide scan of susceptibility of BALB/c mice to thymic lymphomas induced by
-ray irradiation of backcross mice between BALB/c and MSM strains (14). Results indicated the existence of a major BALB/c susceptibility allele near D4Mit12 on chromosome 4 and, interestingly, they also suggested an MSM resistance locus near D5Mit5 on chromosome 5. The linkage of D5Mit5 was only suggestive, however, especially given the concern about the use of multiple statistical tests (15), and hence further study was required to establish the relationship.
Mouse thymic lymphomas can also be induced by chemical carcinogens such as N-methyl-N-nitrosourea (MNU), an alkylating agent that can modify guanine bases in DNA, resulting in mutation to adenine bases after DNA replication. Hence, MNU differs in the mode of action from ionizing radiation, which tends to induce large mutations such as deletion and translocation (16,17). Thus, the putative BALB/c D5Mit5 resistance locus may not affect MNU induction of thymic lymphomas. To characterize the D5Mit5 locus, we have produced congenic mice containing the MSM D5Mit5 region on a BALB/c background, and examined lymphoma development in their progeny after
-ray irradiation or MNU administration. Here we show a highly significant linkage between the D5Mit7 locus near D5Mit5 and resistance to
-ray induction, but not to MNU induction, of thymic lymphomas. This suggests different effects of the BALB/c allele on carcinogenic action of the two agents in lymphoma development.
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Materials and methods
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Establishment of congenic mice on chromosome 5
Congenic mice were obtained by backcrossing MSM mice to BALB/c according to the marker-assisted protocol using 111 polymorphic markers distributed throughout the genome (18). Homozygotes were established after nine backcrossings. The congenic line harbored the MSM-derived region of 28.4 cM between D5Mit4 and D5Mit315 on chromosome 5. BALB/c mice were purchased from Charles River Japan (Yokohama, Japan) and MSM were kindly provided from T.Shiroishi at the National Institute of Genetics (Mishima, Japan). MSM is an inbred strain derived from Japanese wild mice, Mus musculus molossinus. The congenic mice were mated with BALB/c and the hybrids were further crossed with MSM. A total of 95 and 48 offsprings were subjected to
-irradiation and MNU administration, respectively.
Development of thymic lymphoma
Mice were subjected to
-irradiation of 2.5 Gy four times at a weekly interval, starting at the age of 4 weeks, or mice were given a single i.p. dose, 75 mg/kg body wt, of MNU (Nakarai Co., Kyoto), when they were at an age of 6 weeks. Development of thymic lymphoma was diagnosed by inspection of labored breathing and palpable induration of thymic tumor. Existence of tumors was confirmed upon autopsy of the mice. Mice alive 300 days after irradiation or 250 days after MNU administration were killed and the absence of thymic lymphoma was ascertained.
Genetic analysis
Genotyping and allelic loss analysis were carried out with microsatellite markers as described previously (13,14). Primers for p53 were as follows: 5'-GCTGGATAGGAAAGAGCACAG and 5'-TGAGATGTTGCCCTCAGCAG. Analysis of K-ras mutations at codons 12 and 13 was carried out with SSCP and subsequent direct sequencing. Primers used are 5'-GCCTGCTGAAAATGACTGAG and 5'-TCAAAGCGCACGCAACTGTG.
Association and statistics
2 and P values for association of markers with the development of MNU-induced thymic lymphomas were obtained by
2 test and MantelCox test with StatView-J 5.0 software on a Macintosh personal computer. QTLs were analyzed of the lymphoma incidence with the Map Manager QTXb14 software (19). Evaluation of linkage followed the criteria of Lander and Kruglyak (15). The statistical threshold of the congenic mouse data was corrected for multiple comparisons using the formula, µ(T) = [C + 2
GT2]
(T): C (number of chromosomes) = 1,
(to account for corrected results among linked loci: for backcross with 1 d.f.) = 1, G (genome size in morgans) = 0.284, T (for the
2 statistic with 1 d.f.) = 3.84 and µ(T) = 0.05 or 0.0001. Linkage was taken as significant in the congenic mice when P was <0.0053 and was highly significant when P was <0.00074.
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Results
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A resistance locus at the D5Mit7 locus
Congenic mice used in this study was of BALB/c (C) background and harbored a chromosomal region of 28.4 cM between D5Mit4 and D5Mit315 on chromosome 5 that was derived from the MSM (M) chromosome (Figure 1A). The mice were mated with BALB/c and the hybrids were then crossed with MSM. Offspring obtained were subjected to fractionated
-irradiation. Among a total of 95 mice irradiated, 58 mice developed thymic lymphomas and 32 mice were free of thymic lymphomas or other cancers for 300 days after irradiation. Two of the remaining five mice were diagnosed with systemic leukemias, two others lung cancer and one with infectious disease as determined by macroscopic inspection. The five mice were not included in the present study.

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Fig. 1. Location of the resistance gene near D5Mit7 on chromosome 5. (A) Open and black boxes represent chromosomal regions of BALB/c and MSM, respectively. (B) Distribution of LOD scores on mouse chromosome 5 calculated by using the MapManager/QTXb14 software on a Macintosh personal computer. (C) The cumulative frequency distributions of -ray-induced thymic lymphomas in mice of two different genotypes. C/M, heterozygotes at D5Mit7; M/M, homozygotes at D5Mit7.
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The 90 mice with or without lymphomas were genotyped using seven markers on chromosome 5, D5Mit4, D5Mit81, D5Mit5, D5Mit7, D5Mit10, D5Mit239 and D5Mit315. Thirty-nine mice inherited the BALB/c chromosome 5 from partly heterozygous parental mice and 19 mice received a whole recombinant chromosome bearing the MSM genome without recombination. Among the latter 19 mice, only two were free of thymic lymphomas. Thirty-two mice carried chromosomes that underwent recombination within the congenic region. Table I summarizes lymphoma incidences and
2 test results for their association to each locus. At the D5Mit7 locus the incidence was 87.5% in M/M homozygotes, much higher than that of 46% in C/M heterozygotes, and the lowest P-value was given in
2 test (0.000054). Figure 1B displays the distribution of likelihood ratio statistic values as LOD scores that were calculated using the MapManager/QTX software (19). The D5Mit7 locus near D5Mit5 provided a peak of the distribution. Figure 1C shows the cumulative lymphoma incidences of homozygotes and heterozygotes at the D5Mit7 locus. The two groups showed a marked difference in the incidence and latency (P < 0.0001 in MantelCox test). These results demonstrated the existence of a resistance gene(s) near the D5Mit7 locus.
Susceptibility to MNU induction of thymic lymphomas
Administration of MNU, an alkylating agent, to BALB/c mice induces thymic lymphomas at a high frequency and the latency is shorter than that after by
-irradiation (2022). We therefore examined the effect of the D5Mit7 locus on MNU induction of thymic lymphomas. On the basis of distinct difference in the incidence of radiogenic lymphomas in mice with M/M and C/M genotypes at D5Mit7, we estimated the sample size required for this study. The number of mice calculated was 16 in each group if a one-tailed test was performed with the significance level
= 0.05 and power = 0.8. Accordingly, a total of 48 mice were produced from the congenic line as described in the previous section and subjected to i.p. injection with MNU. The mice were under inspection for 250 days thereafter, as our previous experiment showed that the cumulative incidence of lymphomas reached a near-plateau 250 days after the administration (23).
Among the 48 mice, 32 mice developed thymic lymphomas, 12 mice were free of thymic lymphoma. The remaining three developed systemic leukemias, lung cancer and skin cancer, and were excluded in this study. Association analysis was carried out in the same manner as done with radiation-induced lymphomas. Table II summarizes the results of a
2 test for the association at each locus. All loci provided small
2 values relative to those of the radiation lymphomas, and the value of the D5Mit7 locus was only 0.865 (P = 0.352). Figure 2A displays the distribution of likelihood ratio statistic values. The pattern much differed from that of
-ray induction. Figure 2B shows the cumulative lymphoma incidences of homozygotes and heterozygotes at the D5Mit7 locus. The two groups did not show significant difference in the incidence and latency (P = 0.20 in MantelCox test). Thus, the effect of the D5Mit7 locus on lymphomagenic action differed significantly between
-ray and MNU.

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Fig. 2. Association analysis of MNU-induced thymic lymphomas. (A) Distribution of LOD scores on mouse chromosome 5 calculated using the MapManager/QTXb14 software on a Macintosh personal computer. (B) The cumulative frequency distributions of MNU-induced thymic lymphomas in mice of two different genotypes. C/M, heterozygotes at D4Mit12; M/M, homozygotes at D4Mit12.
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Genetic alterations in thymic lymphomas
Certain susceptibility loci were found to be mutated tumor suppressor genes (13). It is possible therefore that a BALB/c allele near the D5Mit7 locus harbors a functional tumor suppressor gene whose MSM allele is mutated, since the BALB/c allele conferred resistance for the lymphoma development. Hence, allelic loss was examined at the D5Mit7 locus in the lymphomas. The allelic loss was found only in one of 23 tumors examined (4.3%) and moreover, the loss was for the BALB/c allele. This did not support the hypothesis described above.
We showed previously that the three loci, Ikaros, Rit1/Bcl11b and Tlsr7 on chromosomes 11, 12 and 16, respectively, underwent allelic loss at high frequencies in thymic lymphomas (2427). Hence, allelic loss was examined at these loci and the p53 locus, because the D5Mit7 locus could affect genomic instability during
-ray or MNU induction of thymic lymphomas. Figure 3 summarizes the results. All of the four loci showed lower frequencies of the losses in the chemically induced lymphomas than those in the
-ray-induced lymphomas, consistent with previous results (20,21,23). However, no significant difference was observed between C/M heterozygous and M/M homozygous lymphomas of D5Mit7. This suggested that the D5Mit7 locus neither affects the recombination nor deletion frequency of the four tumor suppressor genes.

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Fig. 3. Allelic loss frequencies of Ikaros, p53, Rit1/Bcl11b and Tlsr7 loci on chromosomes 11, 11, 12 and 16, respectively, and the frequency of K-ras mutations. Columns display the fractions of the allelic losses or K-ras mutations in -ray and MNU-induced thymic lymphomas that were developed in mice of C/M or M/M genotypes at D5Mit7. Among two K-ras mutations detected in MNU lymphomas, one is GGT to GAT change of the codon 12, and the other GGT to GTT change of the codon 12.
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K-ras is much more frequently mutated in mouse thymic lymphomas than the other H-ras and N-ras genes and the activation is attributed mostly to single point mutations localized to codon 12 or codon 13 (20,21). Therefore, mutations of the codons 12 and 13 of K-ras gene were examined by SSCP and subsequent sequence analysis. No changes were found in the
-irradiated lymphomas but missense mutations were identified in two of the MNU-induced lymphomas, one being in the C/M lymphomas and the other in the M/M lymphomas (Figure 3). The lower frequency of K-ras mutations in
-irradiated lymphomas is consistent with previous reports (21,23).
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Discussion
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The present study has investigated susceptibility/resistance of BALB/c mice to
-ray-induced thymic lymphomas by examining lymphoma incidence in the progeny of mice congenic for a 28.4 cM region between D5Mit4 and D5Mit315 from the MSM strain. The incidence was 87.5% in mice of the M/M genotype at D5Mit7, much higher than the 46% seen in mice of the C/M genotype (Table I). This is consistent with our previous result by genome scanning of backcross mice (14). The P value in this association study was 0.000054 at D5Mit7, much less than 0.00074 that is the threshold to achieve a false positive rate of 0.1% or less in the analysis of markers on the congenic region (15) (see Materials and methods). We therefore conclude that there is a highly significant linkage between the D5Mit7 locus and the resistance to
-ray induction of thymic lymphomas. We tentatively designated this locus as Lyr3, lymphoma resistance gene 3.
This study also examined the effect of the Lyr3 locus on MNU induction of thymic lymphomas, but no evidence for any linkage was found (Table II). The P value at the D5Mit7 locus was 0.35 in a
2 test and was not centered in the congenic region with the distribution of the likelihood ratio statistics. The result contrasts to that of the
-ray-induced lymphomas. Therefore, Lyr3 does not affect susceptibility to MNU induction of thymic lymphomas or, if any, the effect is much less than that of
-ray induction.
The nature of the Lyr3 gene product remains to be identified. It is possible that tumor susceptibility/resistance genes could be those whose gene products probably have a physiological role in recombination/repair process or in the growth regulation of the target hematopoietic stem cells or common lymphoid progenitors. Otherwise, they may regulate growth of thymocytes during lymphomagenesis through interaction with thymic microenvironment. Genes involved in recombination/repair processes affect the frequency of oncogene activation and inactivation of tumor suppressor genes required for lymphomagenesis. To address this issue, we examined allelic loss frequencies at the Ikaros, p53, Rit1/Bcl11b and Tlsr7 loci on chromosomes 11, 11, 12 and 16, respectively. Comparison between lymphomas of C/M and M/M genotypes at D5Mit7 did not show significant difference in the frequencies of genetic alterations in either radiation or MNU lymphomas (Figure 3). In addition, the K-ras mutation frequency was very low in lymphomas of both genotypes. These results suggest that the resistance locus does not affect the recombination/repair process that increases mutation frequency. McMorrow et al. analyzed the changes in chromosomes in
-ray and MNU-induced thymic lymphomas (28). It was shown that trisomy 15 occurred in both groups of mice regardless of inducing agent and that a marker chromosome comprised of a translocation between chromosomes 1 and 5 occurred only in
-ray-induced lymphomas. It is possible therefore that Lyr3 may affect generation of the marker chromosome in
-ray-induced lymphomas, and this possibility remains to be addressed.
A second possibility is that the resistance operates at the tissue level and decreases the net growth rate by altering the balance between cell division and apoptosis in lymphoid cells in the thymus. Classic studies of radiation induction of mouse thymic lymphomas demonstrated that the unirradiated thymus contributes to the development of the malignancy when transplanted into the kidney capsule of irradiated mice (29). This suggests an important role of the tissue microenvironment in radiation carcinogenesis, which is now well recognized (30). These studies also revealed an involvement of bone marrow cells in lymphoma induction. Fractionated whole-body irradiation causes thymic atrophy and depletion of bone marrow cells, leading to regeneration and differentiation arrest of surviving thymocytes. Interestingly, the lymphomagenesis can be reduced by shielding a very small portion of bone marrow or by bone marrow transplantation shortly after irradiation (7,3134). Potworowski et al. (35) reported that dendritic cells, but not thymocyte precursors, supplied by bone marrow to the thymus play a key role in the prevention of lymphoma development after irradiation. On the other hand, involvement of the thymus and bone marrow is not well studied in thymic lymphomas induced by chemical carcinogens despite similar serological properties of lymphoma cells as those induced by radiation (36). It is noteworthy that the development of DMBA-induced thymic lymphomas was not suppressed by bone marrow transplantation (37,38).
Radiation effects on the thymus and bone marrow can be modified by strain difference. This issue was examined using radiation bone-marrow chimeras between susceptible B10 and resistant C3H or STS strains (39,40). Susceptibility of B10 relative to C3H was ascribed to bone marrow-derived cells, whereas the resistance of STS, but not C3H, was the intrinsic property of thymocytes. Taking into account that bone marrow transplantation can suppress
-ray induction, but not DMBA induction, of thymic lymphomas, it is likely that Lyr3 may affect the property of bone marrow cells or dendritic cells for lymphoma prevention, because Lyr3 influenced susceptibility to radiation-induced but not to MNU-induced lymphomas. Strain difference in apoptosis was also investigated using recombinant congenic strains derived from BALB/c and STS strains (41,42). Association analysis mapped three loci on chromosomes 3, 9 and 16 that gave susceptibility to radiation-induced apoptosis of thymocytes. However, none of the loci on chromosome 5 were implicated. Therefore, Lyr3 may not be involved in apoptosis or thymic atrophy.
We assigned previously a susceptibility locus to
-ray induction of thymic lymphomas to the D4Mit12 locus on chromosome 4 (14). In contrast to the D5Mit7 locus, this locus was involved in susceptibility to both
-ray and MNU induction of thymic lymphomas, suggesting that it may function in tissues other than bone marrow cells, possibly in T cell precursors (23). Therefore, we infer that the D5Mit7 and D4Mit12 loci differently act in modification of lymphomagenesis by the two different carcinogens. This is not surprising, because of the difference in their action of the two carcinogenic agents. First, MNU can induce base changes whereas ionizing radiation induces DNA double-strand breaks and the latter are the principal lesions in the induction of both chromosomal abnormalities and gene mutations (17). Consistently, we observed higher frequencies of allelic losses in radiogenic lymphomas than in MNU-induced lymphomas (Figure 3). Secondly, radiation has an ability to penetrate cells and to deposit energy within them in a random fashion, unaffected by the usual cellular barriers presented to chemical agents. All cells in the body are hence susceptible to damage by ionizing radiation (17). This may provide a biological basis to understand the involvement of tissue microenvironment in carcinogenesis as described above.
Database searches provide a number of genes present within the Lyr3 region, including Sod3, extracellular superoxide dismutase (EC-SOD) gene (43), and Cypr3 that controls expression of IL-4 and IL-10 (44). Mouse and human EC-SOD are secretory glycoproteins of particular interest because they are antioxidant enzymes that can respond to superoxide free-radical anion species. Disregulation of the enzyme expression or function may affect some of the cellular responses after
-irradiation and eventually lymphoma development. RTPCR of RNA from thymus and several other tissues, however, did not show difference in expression of this gene between BALB/c and MSM strains (data not shown). On the other hand, sequence analysis has revealed a polymorphism between the two strains that changes the amino acid of asparagine in BALB/c to aspartic acid in MSM at the 21st position from the first methionine codon (data not shown). Although functional significance of the difference remains to be addressed, this suggests that Sod3 is a candidate for Lyr3. Efforts are now being made to narrow down the resistance region by generating congenic strains harboring smaller MSM-derived regions and testing their lymphoma susceptibility.
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Notes
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6 To whom correspondence should be addressed Email: rykomina{at}med.niigata-u.ac.jp 
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Acknowledgments
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The authors thank A.Balmain for reading the manuscript and helpful comments. We are also grateful to Kohei Akazawa and Kazutoshi Nakamura for statistical analysis. This work was supported by grants-in-aid of Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan.
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References
|
---|
- Balmain,A., Gray,J. and Ponder,B. (2003) The genetics and genomics of cancer. Nature Genet., 33, 238244.[CrossRef][ISI][Medline]
- Ponder,B.A.J. (2001) Cancer genetics. Nature, 411, 336341.[CrossRef][ISI][Medline]
- Demant,P. (1992) Genetic resolution of susceptibility to cancernew perspectives. Cancer Biol., 3, 159166.
- Nadeau,J.H. (2001) Modifier genes in mice and humans. Nature Rev. Genet., 2, 165174.[CrossRef][ISI][Medline]
- Balmain,A. (2002) Cancer as a complex genetic trait: tumor susceptibility in humans and mouse models. Cell, 108, 145152.[ISI][Medline]
- Weinberg,R.A. (1991) Tumor suppressor genes. Science, 254, 11381146.[ISI][Medline]
- Darvasi,A. (1998) Experimental strategies for the genetic dissection of complex traits in animal models. Nature Genet., 18, 1924.[CrossRef][ISI][Medline]
- Kaplan,H.S. and Brown,M.B. (1952) A quantitative dose-response study of lymphoid-tumor development in irradiated C57 black mice. J. Natl Cancer Inst., 13, 185208.[ISI]
- Kaplan,H.S. (1964) The role of radiation in experimental leukemogenesis. Natl Cancer Inst. Monogr., 14, 207217.
- Kaplan,H.S. (1967) On the natural history of the murine leukemias: presidential address. Cancer Res., 27, 13251340.[ISI][Medline]
- Meruelo,D., Offer,M. and Flieger,N. (1981) Genetics of susceptibility to radiation-induced leukemia. J. Exp. Med., 154, 12011211.[Abstract]
- Okumoto,M., Nishikawa,R., Imai,S. and Hilgers,J. (1990) Genetic analysis of resistance to radiation lymphomagenesis with recombinant inbred strains of mice. Cancer Res., 50, 38483850.[Abstract]
- Matsumoto,Y., Kosugi,S., Shinbo,T. et al. (1998) Allelic loss analysis of gamma-ray-induced mouse thymic lymphomas: two candidate tumor suppressor gene loci on chromosomes 12 and 16. Oncogene, 16, 27472754.[CrossRef][ISI][Medline]
- Saito,Y., Ochiai, Y., Kodama,Y. et al. (2001) Genetic loci controlling susceptibility to gamma-ray-induced thymic lymphoma. Oncogene, 20, 52435247.[CrossRef][ISI][Medline]
- Lander,E. and Kruglyak,L. (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet., 11, 241247.[ISI][Medline]
- Goodhead,D.T., Thacker,J. and Cox,R. (1993) Weiss lecture. Effects of radiations of different quantities on cells: molecular mechanisms of damage and repair. Int. J. Radiat. Biol., 63, 543556.[ISI][Medline]
- Little,J.B. (2000) Radiation carcinogenesis. Carcinogenesis, 21, 397404.[Abstract/Free Full Text]
- Markel,P., Shu,P., Ebeling,C., Carlson,G.A., Nagle,D.L., Smutko,J.S. and Moore,K.J. (1997) Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nature Genet., 17, 280284.[ISI][Medline]
- Manly,K.F., Cudmore,R.H.,Jr and Meer,J.M. (2001) Map Manager QTX, cross-platform software for genetic mapping. Mam. Genome, 12, 930932.[CrossRef][ISI]
- Diamond,L.E., Guerrero,I. and Pellicer,A. (1988) Concomitant K- and N-ras gene point mutations in clonal murine lymphoma. Mol. Cell. Biol., 8, 22332236.[ISI][Medline]
- Shimada,Y., Nishimura,M., Kakinuma,S., Takeuchi,T., Ogiu,T., Suzuki,G., Nakata,Y., Sasanuma,S., Mita,K. and Sado,T. (2001) Characteristic association between K-ras gene mutation with loss of heterozygosity in X-ray-induced thymic lymphomas of the B6C3F1 mouse. Int. J. Radiat. Biol., 77, 465473.[CrossRef][ISI][Medline]
- Angel,J.M. and Richie,E.R. (2002) Tlag2, an N-methyl-N-nitrosourea susceptibility locus, maps to mouse chromosome 4. Mol. Carcinogen., 33, 105112.[CrossRef][ISI][Medline]
- Sato,H., Tamura,Y., Ochiai,Y., Kodama,Y., Hatakeyama,K., Niwa,O. and Kominami,R. (2003) The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both
-ray induced and N-methyl-N-nitrosourea-induced thymic lymphomas. Cancer Sci., 94, 668671.[ISI][Medline]
- Okano,H., Saito,Y., Miyazawa,T., Shinbo,T., Chou,D., Kosugi,S., Takahashi,Y., Odani,S., Niwa,O. and Kominami,R. (1999) Homozygous deletions and point mutations of the Ikaros gene in
-ray-induced mouse thymic lymphomas. Oncogene, 18, 66776683.[CrossRef][ISI][Medline]
- Wakabayashi,Y., Inoue,J., Takahashi,Y., Matsuki,A., Kosugi-Okano,H., Shinbo,T., Mishima,Y., Niwa,O. and Kominami,R. (2003) Homozygous deletions and point mutations of the Rit1/Bcl11b gene in
-ray induced mouse thymic lymphomas. Biochem. Biophys. Res. Commun., 301, 598603.[CrossRef][ISI][Medline]
- Wakabayashi,Y., Watanabe,H., Inoue,J. et al. (2003) Bcl11b is required for differentiation and survival of
ß T lymphocytes. Nature Immunol., 4, 533539.[CrossRef][ISI][Medline]
- Matsuki,A., Kosugi-Okano,H., Ochiai,Y., Kosugi,S., Miyazawa,T., Wakabayashi,Y., Hatakeyama,K., Niwa,O. and Kominami,R. (2001) Allelic loss mapping and physical delineation of a region harboring a thymic lymphoma suppressor gene on mouse chromosome 16. Biochem. Biophys. Res. Commun., 282, 1620.[CrossRef][ISI][Medline]
- McMorrow,L.E., Newcomb,E.W. and Pellicer,A. (1988) Identification of a specific marker chromosome early in tumor development in
-irradiated C57BL/6 J mice. Leukemia, 2, 115119.[ISI][Medline]
- Kaplan,H.S., Carnes,W.H., Brown,M.B. and Hiesch,B.B. (1956) Indirect induction of lymphomas in irradiated mice. I. Tumor incidence and morphlogy in mice bearing nonirradiated thymic grafts. Cancer Res., 16, 422425.[ISI][Medline]
- Barcellos-Hoff,M.H. and Brooks,A.L. (2001) Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability. Radiat. Res., 156, 618627.[ISI][Medline]
- Ludwig,F.C., Elashoff,R.M. and Wellington,J.S. (1968) Murine radiation leukemia and the preleukemic state. Lab. Invest., 19, 240251.[ISI]
- Sado,T., Kamisaku,H. and Kubo,E. (1991) Bone marrow-thymus interactions during thymic lymphomagenesis induced by fractionated radiation exposure in B10 mice: analysis using bone marrow transplantation between Thy 1 congenic mice. J. Radiat. Res., 32 (suppl 2), 168180.
- Coggin,J.H.,Jr, Rohrer,J.W. and Barsoum,A.L. (1997) A new immunobiological view of radiation-promoted lymphomagenesis. Int. J. Radiat. Biol., 71, 8194.[CrossRef][ISI][Medline]
- Humblet,C., Defresne,M.P., Greimers,R., Rongy,A.M. and Boniver,J. (1989) Further studies on the mechanism of radiation induced thymic lymphoma prevention by bone marrow transplantation in C57BL mice. Leukemia, 3, 813818.[ISI][Medline]
- Potworowski,E.F., Gagnon,F., Beauchemin,C. and St Pierre,Y. (1996) Dendritic cells prevent radiation-induced thymic lymphoma. Leukemia, 10, 16391647.[ISI][Medline]
- Newcomb,E.W., Steinberg,J.J. and Pellicer,A. (1988) ras oncogenes and phenotypic staging in N-methylnitrosourea- and
-irradiation-induced thymic lymphomas in C57BL/6 J mice. Cancer Res., 48, 55145521.[Abstract]
- Chen,L. (1970) Further studies of the effect of bone marrow cells on chemically induced lymphoma in C57BL-6 mice. Br. J. Cancer, 24, 554560.[ISI][Medline]
- Chen,L. and Berenblum,I. (1968) Failure of syngeneic bone marrow cells to protect against MC-induced lymphoma in dba-2 mice. Br. J. Cancer, 22, 582587.[ISI][Medline]
- Kamisaku,H., Aizawa,S., Tanaka,K., Watanabe,K. and Sado,T. (2000) Different cellular basis for the resistance of C3H and STS strain mice to the development of thymic lymphomas following fractionated whole-body irradiation: analysis using radiation bone marrow chimeras. Int. J. Radiat. Biol., 76, 11051111.[CrossRef][ISI][Medline]
- Kamisaku,H., Aizawa,S., Kitagawa,M., Ikarashi,Y. and Sado,T. (1997) Limiting dilution analysis of T-cell progenitors in the bone marrow of thymic lymphoma-susceptible B10 and -resistant C3H mice after fractionated whole-body X-irradiation. Int. J. Radiat. Biol., 72, 191199.[CrossRef][ISI][Medline]
- Mori,N., Okumoto,M., Hart,A.A. and Demant,P. (1995) Apoptosis susceptibility genes on mouse chromosome 9 (Rapop2) and chromosome 3 (Rapop3). Genomics, 30, 553537.[CrossRef][ISI][Medline]
- Mori,N., Okumoto,M., van der Valk,M.A., Imai,S., Haga,S., Esaki,K., Hart,A.A. and Demant,P. (1995) Genetic dissection of susceptibility to radiation-induced apoptosis of thymocytes and mapping of Rapop1, a novel susceptibility gene. Genomics, 25, 609614.[CrossRef][ISI][Medline]
- Folz,R.J., Guan,J., Seldin,M.F., Oury,T.D., Enghild,J.J. and Crapo,J.D. (1997) Mouse extracellular superoxide dismutase: primary structure, tissue-specific gene expression, chromosomal localization, and lung in situ hybridization. Am. J. Respir. Cell Mol. Biol., 17, 393403.[Abstract/Free Full Text]
- Kosarova,M., Havelkova,H., Krulova,M., Demant,P. and Lipoldova,M. (1999) The production of two Th2 cytokines, interleukin-4 and interleukin-10, is controlled independently by locus Cypr1 and by loci Cypr2 and Cypr3, respectively. Immunogenetics, 49, 134141.[CrossRef][ISI][Medline]
Received July 3, 2003;
revised August 27, 2003;
accepted September 11, 2003.