Assessing lineage infidelity, oncogenic cooperativity and dependency in RUNX1-mutant acute myeloid leukemia

项目摘要/摘要 矮小相关转录因子1(RUNX1)是造血和白血病发生的主要调节因子。 在10-20%的急性髓系白血病(AML)患者中发现了RUNX1突变。RUNX1-突变体 AML具有化疗耐药和预后不良的特点。RUNX1-突变体中普遍存在血统不忠 已被认为是治疗耐药的一种潜在机制。然而，这些机制 通过RUNX1突变赋予AML的血统不忠以及血统不忠对AML的特殊贡献 RUNX1突变型AML的发病机制尚不清楚。导致白血病的RUNX1突变可能 在白血病发生和谱系确定方面具有潜在的突变特异性功能。NRAS突变 是RUNX1突变型AML中最常见的共突变基因，显示出谱系不忠，这表明 NRAS突变与致病RUNX1突变协同促进白血病发生和谱系 不忠。目前的临床前模型包括可诱导的RUNX1缺失小鼠和生殖系RUNX1 R174Q突变 并不理想地适合检验这一假说。在这个提议中，我们将利用一种新的可诱导的、可逆的 Runx1R174Q等位基因，单独或与NRAS疾病等位基因协同作用。这将使我们能够描述 RUNX1的突变特异性功能，突变对白血病转化和谱系的影响 不忠，并解决在白血病启动和维持中对RUNX1突变的要求。这个 该项目的具体目标是：1)表征血统不忠、遗传异质性及其预后 RUNX1-突变型AML的相关性。2)确定Runx1R174Q和Runx1R174Q+的运行机制 NrasG12D可导致白血病发生和血统不忠。3)研究Runx1R174Q突变的必要性 疾病的发起和维护。这些研究将有助于更好地了解疾病的发病机制 以及新的治疗模式，这也将塑造我未来独立实验室的重点。 肖文斌，医学博士，MSKCC助理会员，将作为四年职业生涯的一部分进行这个项目 开发计划，75%的时间用于研究，其余的时间用于临床工作。文斌是 由世界血液系统恶性疾病专家罗斯·莱文博士指导。他还得到了奥马尔医生的建议 MSKCC的Abdel-Wahab、Kristian Helin和Richard Koche，以及阿尔伯特·爱因斯坦学院的Ulrich Steidl博士 医学。他将与生物系的Andriy Derkach博士和Elli Papaemmanuil博士合作- MSKCC的统计数据。文斌的培训将包括获得技术实验室技能，小说知识 双重组酶白血病小鼠模型、表观遗传调控知识和正规训练 生物信息学。在短期内，该项目的目标是就这项研究的结果发表两篇论文。在……里面 从长远来看，目标是开发一个研究计划并获得R01资金，以成为 血液系统恶性肿瘤的独立实验室调查员。

PROJECT SUMMARY/ABSTRACT RUNT-related transcription factor 1 (RUNX1) is a master regulator of hematopoiesis and leukemogenesis. RUNX1 mutations are identified in 10-20% of patients with acute myeloid leukemias (AML). RUNX1-mutant AML is characterized by chemoresistance and poor prognosis. Lineage infidelity is prevalent in RUNX1-mutant AML and has been proposed as a potential mechanism of therapeutic resistance. However, the mechanisms by which RUNX1 mutations confer lineage infidelity in AML and the specific contribution of lineage infidelity to the pathogenesis of RUNX1-mutant AML remain poorly understood. Leukemogenic RUNX1 mutations may possess potential mutant-specific functionalities in leukemogenesis and lineage specification. NRAS mutations are the most common co-mutated genes in RUNX1-mutant AML exhibiting lineage infidelity, suggesting that NRAS mutations cooperate with pathogenic RUNX1 mutations to promote leukemogenesis and lineage infidelity. Current preclinical models including inducible Runx1 null mice and germline Runx1 R174Q mutations are not ideally suited to test this hypothesis. In this proposal, we will utilize a novel inducible, reversible Runx1R174Q allele, alone or together with cooperating Nras disease alleles. This will allow us to characterize the mutant-specific functionalities of RUNX1, the impact of comutations on leukemic transformation and lineage infidelity, and address the requirement for RUNX1 mutations in leukemia initiation and maintenance. The specific aims of this project are: 1) Characterize lineage infidelity, genetic heterogeneity and their prognostic relevance in RUNX1-mutant AML. 2) Determine the mechanisms by which Runx1R174Q and Runx1R174Q + NrasG12D induce leukemogenesis and lineage infidelity. 3) Investigate the necessity of Runx1R174Q mutations in disease initiation and maintenance. These studies will lead to better understanding of disease mechanisms and new modes of therapy, which will also shape the focus of my future independent lab. Wenbin Xiao, MD, PhD, an Assistant Member at MSKCC, will conduct this project as part of a 4-year career development plan, dedicating 75% of his time to research with remainder spent on clinical work. Wenbin is mentored by Dr. Ross Levine, a world expert in hematologic malignancies. He is also advised by Drs. Omar Abdel-Wahab, Kristian Helin and Richard Koche at MSKCC, and Dr. Ulrich Steidl at Albert Einstein College of Medicine. He will collaborate with Dr. Andriy DerKach and Dr. Elli Papaemmanuil both at Department of Bio- Statistics of MSKCC. Wenbin’s training will include gaining technical laboratory skills, knowledge in the novel leukemia mouse model with dual recombinases, knowledge in the epigenetic regulation, and formal training in bioinformatics. In the short term, the project goal is to publish two papers on the findings from this research. In the long term, the goal is for developing a research program and obtaining R01 funding to become an independent laboratory investigator in hematologic malignancies.