Analysis of the role of immune deficiency in E2A-/- T cell lymphomagenesis

 描述(由申请人提供)：T淋巴细胞谱系急性淋巴细胞性白血病是一种发生在儿童和成人中的恶性肿瘤，预计随着美国人口平均年龄的增加，发病率将会增加。虽然多种癌基因和肿瘤抑制基因与该病有关，但超过60%的T-ALL病例具有降低E2A转录因子功能的突变。此外，缺乏E2a蛋白的小鼠会患上类似T-ALL的恶性肿瘤，这一发现导致了E2a蛋白是肿瘤抑制因子的假设。在这项拨款申请中，我们将检验一个相反的假设，即E2A蛋白丢失造成的免疫缺陷会导致早期胸腺细胞前体竞争的丧失，并且这种竞争的丧失会导致T-ALL样疾病的发展。我们将通过测试野生型胸腺祖细胞抑制E2A缺陷胸腺细胞转化的能力，以及测试E2A缺陷小鼠的免疫缺陷程度是否足以利用一种新的胸腺植入模型来促进WT细胞的转化来检验我们的假设。我们还将测试胸腺细胞前体细胞竞争增加对E2A缺陷T细胞前体细胞基因表达程序的影响，以确定受免疫缺陷而不是E2A缺陷调控的基因特征。我们的实验将为T细胞转化的机制提供重要的见解，并可能揭示免疫系统衰退是T-ALL易感性的先兆。

 DESCRIPTION (provided by applicant): T lymphocyte lineage acute lymphoblastic leukemia is a malignancy that occurs in children and adults and is predicted to increase in incidence as the average age of the American population increases. While multiple oncogenes and tumor suppressors have been implicated in this disease greater than 60% of T-ALL cases have mutations that decreased the function of the E2A transcription factors. Moreover, mice lacking E2A proteins develop a T-ALL-like malignancy, a finding that led to the hypothesis that E2A proteins are tumor suppressors. In this grant application we will test an opposing hypothesis, that the immune deficiency created by loss of E2A proteins results in a loss of early thymocyte progenitor competition and that this loss of competition drives the development of T-ALL like disease. We will test our hypothesis by examining the ability of wild-type thymocyte progenitors to suppress transformation of E2A-deficient thymocytes and by testing whether the degree of immune deficiency in E2A-deficient mice is sufficient to promote transformation of WT cells using a novel model of thymic engraftment. We will also test the impact of increasing thymocyte progenitor competition on the gene expression program of E2A-deficient T cell progenitors to identify gene signatures that are regulated by immune deficiency as opposed to E2A-deficiency. Our experiments will provide significant insight into the mechanism of T cell transformation and may reveal that immune system decline is a precursor to T-ALL susceptibility.