Mechanisms of T Cell Tumorigenesis

描述（由申请人提供）：淋巴瘤和白血病是人类常见的癌症。正常淋巴细胞发育包括V(D)J重组，在抗原特异性受体位点产生DNA双链断裂（DSBs），一旦形成功能性重排，随后就会爆发增殖。解除V(D)J重组可能导致发育中的淋巴细胞中持续的dsb，如果刺激其增殖，可能导致基因组不稳定和肿瘤发生。在我们对V(D)J重组调控的研究过程中，我们产生了缺乏T细胞受体(TCR) β位点可变基因片段转录增强子或启动子的突变小鼠。这两种突变都会导致TCR - β重排过程中基因片段的断裂失控，因此，在发育中的胸腺细胞中会出现持续的dsb。一个重排的TCR转基因的表达，促进胸腺细胞增殖，导致T细胞急性淋巴母细胞淋巴瘤（T- all）在两个突变小鼠株的发展。因此，在原癌基因或肿瘤抑制基因缺乏易感突变的情况下，TCR表达与TCR β位点的顺式调控元件突变相互作用，促进T-ALL的发展。本应用程序旨在检查i) TCR β位点上dsb的命运以及它们的分辨率如何有助于肿瘤发生；ii)抑制含有DSBs的胸腺细胞中p53激活在肿瘤发生中的作用，iii)在缺乏增强子或启动子的TCR转基因小鼠中产生T- all的直接前体细胞的身份。所提出的研究结果可能揭示了人类淋巴肿瘤中抗原受体位点频繁易位的病因学和机制。

DESCRIPTION (provided by applicant): Lymphomas and leukemias are frequent cancers in humans. Normal lymphocyte development involves V(D)J recombination, which generates DNA double stand breaks (DSBs) at antigen-specific receptor loci, followed by a burst of proliferation once a functional rearrangement is formed. Deregulation of V(D)J recombination could result in persistent DSBs in developing lymphocytes, which, if stimulated to proliferate, may result in genome instability and tumorigenesis. In the course of our studies on the regulation of V(D)J recombination, we generated mutant mice that lack either the transcriptional enhancer or the promoter of a variable gene segment in the T cell receptor (TCR) beta locus. Either mutation results in deregulated cleavages of gene segments during TCR beta rearrangement and, therefore, persistent DSBs in developing thymocytes. Expression of a rearranged TCR transgene, which promotes thymocyte proliferation, results in the development of T cell acute lymphoblastic lymphoma (T-ALL) in either of the mutant mouse strains. Thus, in the absence of predisposing mutations in proto-oncogenes or tumor suppressor genes, TCR expression interacts with mutations in cis-regulatory elements at the TCR beta locus to promote the development of T-ALL. This application aims to examine i) the fate of DSBs at the TCR beta locus and how their resolution contributes to tumorigenesis; ii) the role of inhibition of p53 activation in thymocytes containing DSBs in tumorigenesis, and iii) the identity of the immediate precursor T cells that give rise to T-ALL in TCR transgenic mice lacking either the enhancer or the promoter. Findings from the proposed studies may shed light on the etiology and mechanisms underlying the frequent translocations of the antigen receptor loci in lymphoid tumors in humans.