"Oncorequisite" Genes in MYC-mediated Transformation

MYC 介导的转化中的“肿瘤必需”基因

基本信息

批准号：
8625712
负责人：
Hui Feng
金额：
$ 23.4万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-03-31
项目状态：
已结题

项目摘要

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 the 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 conducted a dominant genetic modifier screen to identify and study "oncorequisite" genes whose mutation delays the onset of leukemia. My screen pinpointed a specific gene encoding dihydrolipoamide Ssuccinyltransferase (DLST) whose heterozygous inactivation significantly delays the onset of lymphoma/leukemia in zebrafish expressing the Myc oncogene. Zebrafish Dlst was upregulated in tumor cells with Myc overexpression, compared to normal cells without Myc overexpression. In addition, this upreguiation of DLST was associated with an increased fraction of cells in 8 phase and genomic instability. Tumor cells with 50% reduction of Dlst tended to be in G1 phase and morphologically more differentiated with a stable genome. I have clarified the importance of the human ortholog of DLST in T-ALL and found that DLST is aberrantly upregulated in the majority of T-ALL cell lines. Small molecule treatment of both human T-ALL cell lines and zebrafish with lymphoma is effective, leading to less viable cells in vitro and delayed tumor progression in vivo. Hence, I consider the human ortholog of this Kreb's cycle transferase as a promising therapeutic target for treating human T-ALL. During ROO phase of the grant, I will further characterize the importance of DLST in human neuroblastoma pathophysiology (new Aim 1) and identify its synergic genes and pathways (new Aim 2). Meanwhile, I will identify additional "oncorequisite" genes in MYC-mediated transformation through zebrafish genetic screens (Aim 3). The rationale and feasibility of this approach are well-illustrated by my data acquired during the K99 phase.

MYC 是一种强效原癌基因，在人类癌症中广泛异常表达，包括白血病和淋巴瘤。该提案的长期目标是发现能够维持 MYC 驱动的肿瘤，特别是 T 细胞急性淋巴细胞白血病 (T-ALL) 所必需的，以及因此可能作为开发新型分子疗法的有用靶标。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，I 进行了显性遗传修饰筛选，以识别和研究其突变的“癌必需”基因延缓白血病的发病。我的屏幕精确定位了编码二氢硫辛酰胺琥珀酰转移酶的特定基因（DLST）其杂合失活显着延迟了发病表达 Myc 癌基因的斑马鱼中的淋巴瘤/白血病。斑马鱼 Dlst 在肿瘤中上调 Myc 过度表达的细胞与没有 Myc 过度表达的正常细胞相比。此外，这 DLST 的上调与 8 期细胞比例的增加和基因组不稳定有关。 Dlst减少50%的肿瘤细胞倾向于处于G1期并且形态上更加分化具有稳定的基因组。我已经阐明了 DLST 的人类直系同源物在 T-ALL 中的重要性，并发现 DLST 在大多数 T-ALL 细胞系中异常上调。小分子治疗人类 T-ALL细胞系和患有淋巴瘤的斑马鱼有效，导致体外活细胞较少并延迟体内肿瘤进展。因此，我认为该克雷布循环转移酶的人类直系同源物是治疗人类 T-ALL 的有前景的治疗靶点。在赠款的原产地组织阶段，我将进一步描述 DLST 在人类神经母细胞瘤病理生理学中的重要性（新目标 1）并确定其协同基因和途径（新目标 2）。同时，我将在其中确定其他“致癌必需”基因通过斑马鱼遗传筛选进行 MYC 介导的转化（目标 3）。这样做的理由和可行性我在 K99 阶段获得的数据很好地说明了这种方法。