Zebrafish Chemical and Classical Genetics Approach to the Pathogenesis of T-ALL

描述（由申请人提供）：T细胞急性淋巴细胞白血病（T-ALL）是一种T细胞前体细胞癌症，发生于所有年龄段的患者，尤其常见于年龄较大的儿童和青少年。尽管通过强化治疗取得了改善，但T-ALL在25%的儿童和50-70%的成人中仍然是致命的。虽然T-ALL的分子发病机制仍不完全清楚，但MYC癌基因的异常激活是大多数T-ALL病例的中心异常。我们工作的中心假设是，这些患者生存率的最显著改善将是我们对介导T-ALL白血病发生和MYC诱导的肿瘤发生的分子机制的理解的改善。我们已经开发了一种MYC诱导的T-ALL的条件性斑马鱼模型，该模型与人类T-ALL的最常见亚型非常相似。这种斑马鱼模型现在使我们能够充分利用斑马鱼系统作为人类疾病模型的优势，通过正向化学遗传筛选和常规遗传分析。正向化学遗传学而不是常规诱变筛选的性能将使我们能够鉴定小分子可靶向的基因产物，因此除了阐明所涉及的基本生物过程之外，还具有明显的治疗意义。因此，为了揭示介导MYC诱导的肿瘤发生和T细胞白血病发生的机制，本提案的具体目的是：1）在斑马鱼中进行正向化学遗传筛选以鉴定MYC过表达胸腺细胞存活所需的靶向基因和途径，但这些基因和途径与MYC的基本生理功能无关。2)使用这些病变的斑马鱼遗传模型，确定新型T-ALL基因组异常中涉及的基因作为潜在T细胞白血病癌基因和肿瘤抑制基因的功能重要性。Gutierrez博士为指导他的职业发展而组建的导师和顾问团队代表了癌症生物学，斑马鱼遗传学和化学筛选方面的一些世界领先专家，这种环境无疑将为他提供发展成为成功的独立研究者的每一个机会。

DESCRIPTION (provided by applicant): T cell acute lymphoblastic leukemia (T-ALL) is a cancer of T cell precursors that occurs in patients of all ages, and is especially common in older children and adolescents. Despite improvements in outcomes that have been achieved through the intensification of therapy, T-ALL remains fatal in 25% of children and 50-70% of adults. Although the molecular pathogenesis of T-ALL remains incompletely understood, aberrant activation of the MYC oncogene is a central abnormality in most cases of T-ALL, The central hypothesis of our work is that the most significant improvements in survival for these patients will come as a result of improvements in our understanding of the molecular mechanisms that mediate T-ALL leukemogenesis and MYC-induced oncogenesis. We have developed a conditional zebrafish model of MYC-induced T-ALL that closely resembles the most common subtype of human T-ALL. This zebrafish model now allows us to take full advantage of the strengths of the zebrafish system as a model of human disease through the performance of forward chemical genetic screens and conventional genetic analyses. The performance of forward chemical genetic rather than conventional mutagenesis screens will allow us to identify gene products that are targetable by small molecules, thus having obvious therapeutic implications in addition to elucidating the basic biologic processes involved. Thus, in an effort to reveal the mechanisms that mediate MYC-induced oncogenesis and T cell leukemogenesis, the specific aims of this proposal are: 1) To perform a forward chemical genetic screen in the zebrafish to identify targetable genes and pathways that are required for the survival of MYC-overexpressing thymocytes, but that are dispensable for the essential physiologic functions of MYC. 2) To establish the functional importance of genes involved in novel T-ALL genomic abnormalities as potential T-cell leukemia oncogenes and tumor suppressors using zebrafish genetic models of these lesions. The mentor and the group of advisors that Dr. Gutierrez has assembled to guide his career development represent some of the world's leading experts in cancer biology, zebrafish genetics, and chemical screens, and this environment will undoubtedly provide him with every opportunity to develop into a successful independent investigator.