Isolation and characterization of genes involved in radiogenic mouse thymic lymphomas

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Mouse thymic lymphomas are one of the classic models of ionizing radiation-induced malignancies, resulting form a series of somatic mutations. Our results obtained in this project were as follows.1. Whole-body γ-irradiation causes thymic atrophy and most of them eventually develop lymphomas. Thus, atrophic thymus may found precancerous cells. Examination of atrophic thymuses at various times after irradiation revealed that DNA changes occur at Bcl11b and Myc earlier than at Ikaros, Pten, and Notch1, suggesting the order of gene mutations during lymphomagenesis. These successive mutations probably give the cells a growth advantage, so that it forms an expanded clone eventually leading to lymphomas.2. We also examined early effects of γ-ray on ROS levels in vivo because ROS may be a main cause for cancer development. ROS levels were compared between congenic mice of two different Mtf-1 genotypes that show distinct susceptibility to thymic lymphomas. Susceptible mice tended to retain larg … More e thymocytes with higher ROS levels more than resistant mice when examined at 7 days after irradiation. The high retention of such large thymocytes may be the foundation of prelymphoma cells.3. Recurrent chromosomal rearrangements at BCL11B are found in human hematopoietic malignancies mostly of T-cell origin. We showed that Bcl11b+/-p53+/-mice exhibit greater susceptibility to lymphomas than Bcl11b+/+p53+/-mice but most lymphomas retained and expressed the wild-type Bcl11b allele. This suggests that Bcl11b is haploinsufficient for suppression of thymic lymphoma development in mice of the p53+/-background.4. Thymocytes of Bcl11b-/-newborn mice exhibit apoptosis at a certain developmental stage when thymocytes reenter into the cell cycle. We showed that Bcl11b-knockdown T-cell lines, when exposed to growth stimuli, exhibit apoptosis at the S phase, consistent with in the in vivo result. The apoptosis was accompanied with decreases in a cell-cycle inhibitor, p27, and an anti-apoptotic protein, Bcl-xL, due to transcriptional repression. This repression was a likely consequence of the impairment of Sirt1, a NAD-dependent deacetylase associating with Bcl11b. These results implicate Bcl11b in the remedy for DNA replication stress and maintenance of genomic integrity. Less