"Oncorequisite" Genes in MYC-mediated Transformation

描述（由申请人提供）：MYC是一种有效的原癌基因，在人类癌症（包括白血病和淋巴瘤）中异常且广泛表达。该提案的长期目标是发现维持MYC驱动的肿瘤所必需的分子，特别是T细胞急性淋巴细胞白血病（T-ALL），因此可能成为开发新型分子治疗剂的有用靶标。使用转基因斑马鱼模型，其中小鼠Myc在胸腺细胞中表达并可靠地产生T细胞白血病，我计划进行显性遗传修饰筛选，以识别和研究突变延迟白血病发作的“癌必需”基因（目的1和2），然后阐明这些基因的人类直系同源物在T-ALL和神经母细胞瘤病理生理学中的重要性，包括其抑制的后果（目标3）。这种方法的原理和可行性很好地说明了我最近的初步数据，精确定位一个特定的基因，编码二氢硫辛酰胺S-琥珀酰转移酶（DLST），其杂合失活显着延迟了淋巴瘤/白血病在表达MYC癌基因的斑马鱼的发病。α-酮基-对甲基-正戊酸（KMV）对α-酮戊二酸脱氢酶复合物（DLST是一种2磅组分）的小分子抑制促进了斑马鱼淋巴瘤/白血病的快速消退，并显著降低了人T-ALL细胞系的活力。因此，我认为人类直系同源物的这种克雷布氏循环转移酶一个有前途的候选人“oncohesisonal”蛋白进一步表征和测试与可用的抑制剂在人类恶性肿瘤。在斑马鱼中使用无偏正向遗传策略将避免对MYC诱导的癌症中的贡献基因和途径的先验知识的需要-这一创新将该应用与该领域的其他应用区分开来-因此，我鉴定的任何抑制突变体将自动成为小分子或单克隆抗体抑制的潜在有用靶点。 相关性：许多人类癌症依赖于MYC癌基因的表达来支持。通过鉴定延迟鱼类Myc驱动的T细胞白血病发作的突变基因，该项目旨在发现可作为人类癌症治疗干预有用靶点的分子。

DESCRIPTION (provided by applicant): MYC, a potent proto-oncogene, is aberrantly and widely expressed in human cancers, including the leukemias and lymphomas. The long-term goal of this proposal is to discover molecules that are necessary to sustain MYC-driven tumors, T-cell acute lymphoblastic leukemia (T-ALL) in particular and hence might serve as useful targets for the development of novel molecular therapeutics. Using a transgenic zebrafish model in which murine Myc is expressed in thymocytes and reliably generates T-cell leukemia, I plan to conduct a dominant genetic modifier screen to identify and study "oncorequisite" genes whose mutation delays the onset of leukemia (Aims 1 and 2) and then to clarify the importance of the human orthologs of these genes in T-ALL and neuroblastoma pathophysiology, including the consequences of their inhibition (Aim 3). The rationale and feasibility of this approach are well-illustrated by my recent preliminary data pinpointing a specific gene, encoding dihydrolipoamide S-succinyltransferase (DLST), whose heterozygous inactivation significantly delayed the onset of lymphoma/leukemia in zebrafish expressing the MYC oncogene. Small molecule inhibition of the cc- ketoglutatate dehydrogenase complex (DLST is an pound2 component) by a-keto-p-methyl-n valeric acid (KMV) promoted the rapid regression of zebrafish lymphoma/leukemia, and significantly decreased the viability of humanT-ALL cell lines. Hence, I consider the human ortholog of this Kreb's cycle transferase a promising candidate "oncorequisite" protein for further characterization and testing with available inhibitors in human malignancies. The use of unbiased forward genetic strategies in the zebrafish will circumvent the need for a priori knowledge of contributing genes and pathways in MYC-induced cancer -an innovation that sets this application apart from others in the field - so that any suppressor mutant I identify will automatically qualify as a potentially useful target for inhibition with small molecules or monoclonal antibodies. RELEVANCE: Many human cancers rely on expression of the MYC oncogene for their support. By identifying mutant genes that delay the onset of Myc-driven T-cell leukemia in fish, this project seeks to discover molecules that could serve as useful targets for therapeutic intervention in human cancers.