Defining novel genetic dependencies in spliceosome mutant leukemia

项目摘要和摘要 候选人：我是奥马尔·阿卜杜勒-瓦哈布博士的人类实验室的博士后研究员 纪念斯隆-凯特琳癌症中心的肿瘤学和病因学项目。我目前的研究 主要介绍白血病中剪接因子突变的发病机制和治疗方法。我们之前演示过 剪接体突变的白血病比野生型更容易受到剪接调节化合物的影响 白血病。根据这些观察，我们现在系统地定义了以前未知的基因 剪接体突变白血病的依赖性，以确定可以在临床上翻译的可操作靶点。 建议的研究将形成一个坚实的平台，我可以在这个平台上建立自己的研究小组 K99奖获得期。我的长期职业目标是建立一个研究项目，专注于 正常和恶性造血的分子调控，具有强烈的基础翻译承诺 将科学发现带入临床。我已经制定了一项有针对性的培训计划，以确保我成功地 成为一名独立的研究人员：(1)拓宽我的科学视野和实验技能；(2)提高 领导力潜能和专业发展；。(3)成立独立委员会，监督我的 培训进展，以及(4)在R00阶段过渡到终身教职轨道研究独立。 研究：编码RNA剪接因子SF3B1、SRSF2和U2AF1基因的获得性突变 代表了白血病中最普遍的一类基因改变。这些突变以杂合子的形式出现。 特定热点上的点突变和RNA剪接中的功能变化。除了 MDS-RARS患者中，髓系白血病的剪接体突变与不良的临床结局相关。 尽管我们之前已经表明，剪接体突变白血病更容易患上 剪接的药物调节，突变白血病中的其他易感性尚不清楚。我们的目标是 定义剪接体突变型白血病特有的遗传依赖性。具体目标是：(1)确定 白血病剪接体突变互斥的机制基础，(2)定义新的基因 剪接体突变型白血病特有的依赖性，以及(3)研究突变型SF3B1- MAP3K7错配在白血病发病机制和治疗中的作用 环境：作为Abdel-Wahab实验室的成员，我们是人类肿瘤学和 MSKCC的致病计划(HOPP)，一个专门从事基于机制的研究的部门 先进的临床翻译。在查尔斯·索耶斯博士的领导下，霍普以其高度 协作环境，以促进翻译研究工作，如本申请中建议的工作。

PROJECT SUMMARY AND ABSTRACT CANDIDATE: I am a postdoctoral research fellow in Dr. Omar Abdel-Wahab's laboratory at the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. My current research focuses on pathogenesis and therapy of splicing factor mutations in leukemias. We previously demonstrated that spliceosome-mutant leukemias are more susceptible to splicing modulatory compounds than wildtype leukemia. Extending from these observations, we are now systematically defining previously unknown genetic dependencies in spliceosome mutant leukemias to identify actionable targets that can be translated clinically. The proposed research will form a solid platform from which I can establish my own research group by the end of the K99 Award period. My long-term career goal is to establish a research program focusing on the molecular regulation of normal and malignant hematopoiesis, with a strong commitment to translate basic scientific discoveries into the clinic. I have developed a focused training plan to ensure my success to becoming an independent investigator: (1) broaden my scientific scope and experimental skillsets; (2) enhance leadership potential and professional development; (3) establish an independent committee to oversee on my training progress, and (4) transition into tenure-track research independence in the R00 phase. RESEARCH: Acquired mutations in genes encoding the RNA splicing factors SF3B1, SRSF2 and U2AF1 represent the most prevalent class of genetic alterations in leukemias. These mutations occur as heterozygous point mutations at specific hot-spots and confer functional alterations in RNA splicing. With the exception of MDS-RARS patients, spliceosome mutations in myeloid leukemias are correlated with poor clinical outcome. Although we have previously shown that spliceosome-mutant leukemias are more susceptible to pharmacologic modulation of splicing, additional vulnerabilities in mutant leukemias are unknown. We aim to define the genetic dependencies unique to spliceosome mutant leukemias. The Specific Aims are: (1) identify the mechanistic basis for mutual exclusivity of spliceosome mutations in leukemias, (2) define novel genetic dependencies specific to spliceosome mutant leukemias, and (3) investigate the role of mutant SF3B1- mediated MAP3K7 mis-splicing in the pathogenesis and therapy of leukemia. ENVIRONMENT: As a member of the Abdel-Wahab laboratory, we are part of the Human Oncology and Pathogenesis Program (HOPP) at MSKCC, a department that specializes in mechanism-based research to advance clinical translation. Under the leadership of Dr. Charles Sawyers, HOPP is known for its highly collaborative environment to facilitate translational research efforts such as those proposed in this application.