Defining novel genetic dependencies in spliceosome mutant leukemia

定义剪接体突变白血病的新遗传依赖性

• 批准号: 10601425
• 负责人: Stanley Chun-Wei Lee
• 金额: $ 7.75万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601425
• 关键词: Affect; Award; Biological; Biological Assay; Cells; Clinic; Clinical; Dependence; Development; Disease; Disease Progression; Dysmyelopoietic Syndromes; Ensure; Epithelial; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Goals; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic stem cells; Hot Spot; Human; In Vitro; Interferons; Knowledge; Laboratories; Leadership; Leukemic Cell; Link; MAP Kinase Gene; MAP3K7 gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Memorial Sloan-Kettering Cancer Center; Messenger RNA; Mind; Molecular; Mutate; Mutation; Myeloid Leukemia; Myeloproliferative disease; NF-kappa B; NFKB Signaling Pathway; Oncology; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phase; Phosphotransferases; Point Mutation; Positioning Attribute; Prognosis; RNA Splicing; RNA interference screen; Recurrence; Refractory Anemia with Ringed Sideroblasts; Regulation; Research; Research Personnel; Research Proposals; Role; SRSF2 gene; Signal Transduction; Solid; Somatic Mutation; Spliced Genes; Spliceosomes; Therapeutic; Therapeutic Uses; Training; Transforming Growth Factor beta; Translating; Translational Research; Validation; base; cancer genome; career; clinical translation; cohort; collaborative environment; design; genome sequencing; improved; inhibitor; insight; leukemia; leukemic transformation; leukemogenesis; mRNA Precursor; member; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; p38 Mitogen Activated Protein Kinase; programs; success; tenure track

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.

项目总结和摘要 候选人：我是奥马尔·阿卜杜勒-瓦哈卜博士在人类科学院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发病机制项目。我目前的研究 主要研究白血病剪接因子突变的发病机制和治疗。我们先前表明 剪接体突变型白血病比野生型白血病对剪接调节化合物更敏感 白血病根据这些观察，我们现在正在系统地定义以前未知的遗传学。 在剪接体突变白血病的依赖性，以确定可在临床上翻译的可操作的目标。 建议的研究将形成一个坚实的平台，从我可以建立自己的研究小组的结束 在K99奖期间。我的长期职业目标是建立一个研究项目， 正常和恶性造血的分子调控，具有强有力的承诺，以翻译基本的 将科学发现带入临床我已经制定了一个重点培训计划，以确保我的成功， 成为一名独立的研究者：（1）扩大我的科学范围和实验技能;（2）提高 领导潜质及专业发展;（3）成立独立委员会， 培训进展，以及（4）过渡到终身制轨道研究独立的R 00阶段。 研究：编码RNA剪接因子SF 3B 1、SRSF 2和U2 AF 1的基因中的获得性突变 代表白血病中最普遍的一类遗传变异。这些突变以杂合子的形式发生 点突变在特定的热点和赋予功能的改变RNA剪接。但不包括 在MDS-RARS患者中，髓系白血病中的剪接体突变与不良临床结局相关。 尽管我们之前已经证明剪接体突变型白血病更容易受到 由于剪接的药理学调节，突变型白血病中的其他脆弱性是未知的。我们的目标是 定义了剪接体突变白血病特有的遗传依赖性。具体目标是：（1）识别 白血病中剪接体突变相互排斥的机制基础，（2）定义新的遗传学 特异性剪接体突变白血病的依赖性，和（3）研究突变SF 3B 1- 介导的MAP 3 K7错误剪接在白血病发病机制和治疗中的作用。 环境：作为Abdel-Wahab实验室的一员，我们是人类肿瘤学的一部分， 发病机制计划（HOPP）在MSKCC，一个部门，专门从事机制为基础的研究， 先进的临床翻译。在Charles Sawyers博士的领导下，HOPP以其高度的 协作环境，以促进转化研究工作，如本申请中提出的那些。