Mechanisms of T Cell Tumorigenesis

描述(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包括V(D)J重组，它在抗原特异的受体基因上产生DNA双链断裂(DSB)，随后一旦形成功能重排，就会爆发增殖。V(D)J重组的解除调控可能导致发育中的淋巴细胞持续DSB，如果被刺激增殖，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，我们产生了缺乏转录增强子或T细胞受体(TCR)β基因座可变基因片段启动子的突变小鼠。任何一种突变都会导致TCRβ重排过程中基因片段的非调控切割，从而导致发育中的胸腺细胞中持续的双链断裂。表达重排的TCR转基因促进胸腺细胞的增殖，导致T细胞急性淋巴母细胞性淋巴瘤(T-ALL)在这两个突变品系的小鼠中发展。因此，在原癌基因或抑癌基因没有易感突变的情况下，TCR的表达与TCRβ基因的顺式调节元件突变相互作用，促进T-ALL的发展。这项应用旨在研究：1)TCRβ基因上DSB的命运及其分解如何有助于肿瘤的发生；ii)在含有DSB的胸腺细胞中抑制P53激活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。这项拟议研究的结果可能有助于阐明人类淋巴系统肿瘤中抗原受体基因座频繁易位的病因和机制。

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.