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

评估 RUNX1 突变急性髓系白血病的谱系不忠、致癌协同性和依赖性

基本信息

批准号：
10351421
负责人：
Wenbin Xiao
金额：
$ 26.42万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-22 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10351421
关键词：
Acute Myelocytic Leukemia Address Alleles Antigens Attenuated Automobile Driving Bioinformatics Biometry Cells Chemoresistance Clinical Data Dependence Development Development Plans Disease Doctor of Philosophy Embryo Epigenetic Process Event Exhibits Funding Future Gene Expression Profile Genes Genetic Genetic Heterogeneity Goals Hematologic Neoplasms Hematopoiesis Hematopoietic stem cells Knockout Mice Knowledge Laboratories Lymphoid Maintenance Mediating Medicine Memorial Sloan-Kettering Cancer Center Mentors Modeling Molecular Mus Mutate Mutation Myelogenous Myeloproliferative disease Oncogenic Output Paper Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Play Pre-Clinical Model Prognosis Publishing RUNX1 gene Recurrence Research Research Personnel Resolution Role Sampling Shapes Techniques Testing Therapeutic Time Training Work acute myeloid leukemia 1 protein career development cohort college epigenetic regulation epigenomics gene regulatory network leukemia leukemic transformation leukemogenesis member mouse model mutant mutant mouse model new therapeutic target novel prognostic programs recombinase restoration skills therapy resistant transcriptomics

项目摘要

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.

项目摘要/摘要与Runt相关的转录因子1（Runx1）是造血和白血病发生的主要调节剂。在10-20％的急性髓样白血病（AML）患者中发现了RUNX1突变。 runx1突变 AML的特征是化学抗性和预后不良。谱系不忠在Runx1突变中普遍存在 AML并已被认为是理论抗性的潜在机制。但是，机制 runx1突变会议会议谱系在AML中的不忠和谱系不忠对 Runx1突变剂AML的发病机理仍然了解不足。白血病runx1突变可能在白血病和谱系规范中具有潜在的突变特异性功能。 NRAS突变是表现出谱系不忠的runx1突变剂中最常见的共突出基因，表明 NRAS突变与致病性RUNX1突变合作，以促进白血病和谱系不忠。当前的临床前模型，包括诱导runx1 null小鼠和种系Runx1 R174Q突变理想地不适合检验这一假设。在此提案中，我们将利用一种新颖的诱导，可逆的 RUNX1R174Q等位基因，单独或与合作的NRAS病等位基因一起。这将使我们能够表征 Runx1的突变特异性功能，合件对白血病转化和血统的影响不忠，并满足白血病倡议和维护中Runx1突变的要求。该项目的具体目的是：1）表征谱系不忠，遗传异质性及其预后与runx1突变aml相关。 2）确定RUNX1R174Q和RUNX1R174Q +的机制 NRASG12D诱导白血病和谱系不忠。 3）研究RUNX1R174Q突变的必要性疾病倡议和维护。这些研究将使人们更好地了解疾病机制以及新的治疗方式，这也将塑造我未来独立实验室的重点。 MSKCC助理成员的医学博士Wenbin Xiao将作为4年职业生涯的一部分进行该项目发展计划，奉献精神的时间占他在临床工作上的剩余时间进行研究。温宾是由血液学恶性肿瘤的世界专家罗斯·莱文（Ross Levine）指导。博士也建议他。奥马尔 MSKCC的Abdel-Wahab，Kristian Helin和Richard Koche以及Albert Einstein College的Ulrich Steidl博士药品。他将与Andriy Derkach博士和Elli Papaemmanuil博士合作。 MSKCC的统计数据。温宾的培训将包括获得技术实验室技能，在小说中知道具有双重重组酶的白血病小鼠模型，表观遗传调节的知识以及对生物信息学。在短期内，项目目标是发表有关这项研究结果的两篇论文。在从长远来看，目标是制定研究计划并获得R01资金，以成为独立实验室研究人员血液系统恶性肿瘤。