ABSTRACT
Bcl11b is a haploinsufficient tumor suppressor gene and expressed in many tissues such as thymus, brain and skin. Irradiated Bcl11b+/- heterozygous mice mostly develop thymic lymphomas, but the preference of Bcl11b inactivation for thymic lymphomas remains to be addressed. We produced Bcl11b+/- heterozygous and Bcl11b wild-type mice of p53+/- background and compared their incidence of gamma-ray induced thymic lymphomas. Majority of the tumors in p53+/- mice were skin tumors, and only 5 (36%) of the 14 tumors were thymic lymphomas. In contrast, Bcl11b+/-p53+/- doubly heterozygous mice developed thymic lymphomas at the frequency of 27 (79%) of the 34 tumors developed (P=0.008). This indicates the preference of Bcl11b impairment for thymic lymphoma development. We also analyzed loss of the wild-type alleles in the 27 lymphomas, a predicted consequence given by gamma-irradiation. However, the loss frequency was low, only six (22%) for Bcl11b and five (19%) for p53. The frequencies did not differ from those of spontaneously developed thymic lymphomas in the doubly heterozygous mice, though the latency of lymphoma development markedly differed between them. This suggests that the main contribution of irradiation at least in those mice is not for the tumor initiation by inducing allelic losses but probably for the promotion of thymic lymphoma development.
Subject(s)
DNA-Binding Proteins/genetics , Genetic Predisposition to Disease , Lymphoma/genetics , Neoplasms, Radiation-Induced/genetics , Repressor Proteins/genetics , Thymus Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Animals , Gamma Rays , Genotype , Loss of Heterozygosity , Mice , Mice, Knockout , PTEN Phosphohydrolase/genetics , Tumor Suppressor Protein p53/geneticsABSTRACT
Recurrent chromosomal rearrangements at BCL11B are found in human hematopoietic malignancies mostly of T-cell origin. However, it is unclear how this disruption contributes to oncogenesis, because the majority of leukemias express BCL11B from an undisrupted allele. Here, we show that Bcl11b(+/-)p53(+/-) mice exhibited greater susceptibility to lymphomas than Bcl11b(+/+)p53(+/-) mice but most lymphomas retained and expressed the wild-type Bcl11b allele. This strongly suggests that Bcl11b is haploinsufficient for suppression of thymic lymphoma development in mice of the p53(+/-) background, a situation in which functional loss of only one allele confers a selective advantage for tumor growth. The haploinsufficiency is further supported by that Bcl11b(+/-) mouse embryos were impaired in thymocyte development and survival. These results indicate relevance of BCL11B aberration to human leukemogenesis.
Subject(s)
DNA-Binding Proteins/genetics , Repressor Proteins/genetics , Tumor Suppressor Proteins/genetics , Animals , Base Sequence , Cell Differentiation , DNA Primers , DNA-Binding Proteins/immunology , Flow Cytometry , Gamma Rays , Genes, Tumor Suppressor , Genetic Predisposition to Disease , Genotype , Haplotypes , Lymphoma/genetics , Mice , Mice, Inbred BALB C , Repressor Proteins/immunology , Thymus Gland/cytology , Thymus Neoplasms/genetics , Tumor Suppressor Proteins/immunologyABSTRACT
Mouse thymic lymphomas are readily induced by radiation and also arise without irradiation when the mice are null in Trp53 functions. In the present study, spontaneous thymic lymphomas in Trp53-/- mice were compared to those arising in irradiated Trp53+/- mice, revealing three features characteristic of the spontaneous lymphomas. (1) Mp53D2, a Trp53 modifier that affects the latent period of radiogenic thymic lymphomas in Trp53+/- mice, had no effect on the development of spontaneous lymphomas. (2) A sex difference in the latency was found. (3) A marked difference was noted in the frequency of allelic loss at the Ikaros gene on chromosome 11, encoding a transcription factor required for normal lymphocyte development and differentiation; 2% in the lymphomas of Trp53-/- mice and 78% in the radiogenic lymphomas of Trp53+/- mice, suggesting that loss of Trp53 may reduce the requirement for the loss of Ikaros for lymphomagenesis. Furthermore, allelic loss analysis on chromosome 19 localized a region that may harbor an unknown tumor suppressor gene. These results suggest intricate steps of lymphomagenesis influenced by the presence or absence of Trp53.
Subject(s)
Genetic Predisposition to Disease/genetics , Lymphoma/metabolism , Neoplasms, Radiation-Induced/metabolism , Thymus Neoplasms/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Animals , Female , Lymphoma/genetics , Male , Mice , Mice, Inbred C57BL , Neoplasms, Radiation-Induced/genetics , Radiation Dosage , Thymus Neoplasms/genetics , Whole-Body Irradiation/adverse effectsABSTRACT
Genetic predisposition to cancers is significant to public health because a high proportion of cancers probably arise in a susceptible human subpopulation. Using a mouse model of gamma-ray-induced thymic lymphomas, we performed linkage analysis and haplotype mapping that suggested Mtf-1, metal-responsive transcription factor-1 (Mtf-1), as a candidate lymphoma susceptibility gene. Sequence analysis revealed a polymorphism of Mtf-1 that alters the corresponding amino acid at position 424 in the proline-rich domain from a serine in susceptibility strains to proline in resistant strains. The transcriptional activity of Mtf-1 encoding serine and proline was compared by transfecting the DNA to Mtf-1-null cells, and the change to proline conferred a higher metal responsiveness in transfections. Furthermore, the resistant congenic strains possessing the Mtf-1 allele of proline type exhibited higher radiation inducibility of target genes than susceptible background strains having the Mtf-1 allele of serine type. Since products of the targets such as metallothionein are able to suppress cellular stresses generated by irradiation, these results suggest that highly inducible strains having Mtf-1 of proline type are refractory to radiation effects and hence are resistant to lymphoma development.
Subject(s)
Lymphoma/genetics , Neoplasms, Radiation-Induced/genetics , Polymorphism, Single Nucleotide/genetics , Thymus Neoplasms/genetics , Transcription Factors/genetics , Amino Acid Sequence , Amino Acid Substitution , Animals , Base Sequence , Cell Line, Tumor , DNA Primers , DNA-Binding Proteins , Disease Models, Animal , Genetic Markers , Genetic Predisposition to Disease , Genetic Variation , Immunity, Innate , Mice , Mice, Inbred BALB C , Proline , Serine , Transfection , Transcription Factor MTF-1ABSTRACT
Susceptibility to gamma-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 gamma-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 chi2 test). These results confirm the presence of a resistance allele for gamma-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.
