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。正常的淋巴细胞发育涉及V（D）J重组，其在抗原特异性受体位点产生DNA双链断裂（DSB），随后一旦形成功能性重排就爆发增殖。V（D）J重组的失调可能导致发育中的淋巴细胞中的持续DSB，如果刺激增殖，可能导致基因组不稳定和肿瘤发生。在我们研究V（D）J重组调控的过程中，我们产生了缺乏T细胞受体（TCR）β基因座中可变基因片段的转录增强子或启动子的突变小鼠。任一突变导致TCR β重排过程中基因片段的裂解失调，因此在发育中的胸腺细胞中产生持续的DSB。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性淋巴瘤（T-ALL）的发展，在任何突变小鼠品系。因此，在原癌基因或肿瘤抑制基因中不存在诱发突变的情况下，TCR表达与TCR β基因座处的顺式调节元件中的突变相互作用以促进T-ALL的发展。本申请旨在研究i）TCR β基因座处DSB的命运以及它们的消退如何有助于肿瘤发生; ii）抑制含有DSB的胸腺细胞中p53活化在肿瘤发生中的作用，以及iii）在缺乏增强子或启动子的TCR转基因小鼠中引起T-ALL的直接前体T细胞的身份。从拟议的研究结果可能揭示的病因和机制的抗原受体位点在人类淋巴肿瘤中频繁易位。

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.