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Isolation and characterization of genes involved in radiogenic mouse thymic lymphomas

放射性小鼠胸腺淋巴瘤相关基因的分离和表征

基本信息

批准号：
15201011
负责人：
KOMINAMI Ryo
金额：
$ 27.21万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

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

小鼠胸腺淋巴瘤是电离辐射诱发恶性肿瘤的经典模型之一，是由一系列体细胞突变引起的。我们在本项目中取得的成果如下：1.全身γ辐射会导致胸腺萎缩，其中大多数人最终会患上淋巴瘤。因此，萎缩的胸腺可能会发现癌前细胞。在照射后不同时间对萎缩的胸腺进行检查，发现Bcl11b和Myc比Ikaros、Pten和Notch1更早发生DNA变化，提示了淋巴肿大过程中基因突变的顺序。这些连续的突变可能使细胞具有生长优势，因此它形成了一个扩张的克隆，最终导致淋巴瘤。我们还检查了γ射线对体内ROS水平的早期影响，因为ROS可能是癌症发生的主要原因。比较了两种不同MTF-1基因型鼠的ROS水平，这两种基因型鼠对胸腺淋巴瘤有不同的易感性。易感小鼠倾向于保留大…在照射后7天检查时，具有更高ROS水平的e胸腺细胞多于耐药小鼠。如此大的胸腺细胞的高度滞留可能是淋巴瘤前细胞的基础。在人类血液系统恶性肿瘤中发现了BCL11B重复的染色体重排，主要是T细胞起源的。我们发现Bcl11b+/-P53+/-小鼠比Bcl11b+/+P53+/-小鼠表现出更高的淋巴瘤易感性，但大多数淋巴瘤保留并表达野生型Bcl11b等位基因。这表明Bcl11b在抑制P53+/-背景的小鼠胸腺淋巴瘤的发展方面存在单倍性不足。Bcl11b-/-新生小鼠胸腺细胞重新进入细胞周期后，在一定发育阶段出现细胞凋亡。我们发现，Bcl11b基因敲除的T细胞系在生长刺激下，出现S时相的凋亡，这与体内的结果一致。细胞凋亡伴随着细胞周期抑制蛋白p27和抗凋亡蛋白bclxl的减少，这是由于转录抑制所致。这种抑制可能是Sirt1受损的结果，Sirt1是一种依赖于NAD的与Bcl11b相关的脱乙酰酶。这些结果表明，Bcl11b在DNA复制应激和维持基因组完整性方面具有补救作用。较少