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

• 批准号: 10670048
• 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
• 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/10670048
• 关键词: Acute Myelocytic Leukemia; Address; Alleles; Antigens; Attenuated; Automobile Driving; Bioinformatics; Biometry; Cells; Chemoresistance; Clinical; Collaborations; Data; Dedications; 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; Immunophenotyping; 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; Recurrence; Research; Research Personnel; Resolution; Role; Sampling; Shapes; Specific qualifier value; Techniques; Testing; 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

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.

项目概要/摘要 RUNT 相关转录因子 1 (RUNX1) 是造血和白血病发生的主要调节因子。 10-20% 的 RUNX1 突变患者存在 RUNX1 突变。 AML 的特点是化疗耐药和谱系不忠在 RUNX1 突变体中普遍存在。 AML 已被提议作为治疗耐药的潜在机制。 RUNX1 突变导致 AML 中的谱系不忠，以及谱系不忠对 AML 的具体贡献 RUNX1 突变 AML 的发病机制目前仍知之甚少。 在白血病发生和 NRAS 突变中具有潜在的突变特异性功能。 是 RUNX1 突变 AML 中最常见的共突变基因，表现出谱系不忠，表明 NRAS 突变与致病性 RUNX1 突变协同促进白血病发生和谱系 目前的临床前模型包括可诱导的 Runx1 缺失小鼠和种系 Runx1 R174Q 突变。 并不非常适合检验这个假设，在这个提案中，我们将利用一种新颖的可诱导的、可逆的。 Runx1R174Q 等位基因，单独或与协同 Nras 疾病等位基因一起，这将使我们能够表征疾病。 RUNX1的突变体特异性功能，换相对白血病转化和谱系的影响 不忠，并解决白血病起始和维持中 RUNX1 突变的要求。 该项目的具体目标是：1）描述谱系不忠、遗传异质性及其预后 RUNX1 突变 AML 中的相关性 2) 确定 Runx1R174Q 和 Runx1R174Q + 的机制。 NrasG12D 诱导白血病发生和谱系不忠 3) 研究 Runx1R174Q 突变的必要性。 这些研究将有助于更好地了解疾病机制。 以及新的治疗模式，这也将塑造我未来独立实验室的重点。 肖文斌博士是 MSKCC 的助理会员，他将在 4 年职业生涯中开展该项目 文斌将75%的时间用于研究，其余时间用于临床工作。 由世界血液恶性肿瘤专家 Ross Levine 博士指导。 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 他将与生物系的 Andriy DerKach 博士和 Elli Papaemmanuil 博士合作。 MSKCC的统计培训将包括获得技术实验室技能、小说知识。 具有双重组酶的白血病小鼠模型、表观遗传调控知识以及正式培训 短期内，该项目的目标是发表两篇关于该研究结果的论文。 从长远来看，目标是开发研究计划并获得 R01 资金，成为 血液系统恶性肿瘤的独立实验室调查员。

项目成果

Clonal hematopoiesis in diffuse large B-cell lymphoma: clinical impact and genetic relatedness to lymphoma and therapy-related myeloid neoplasm.

弥漫性大 B 细胞淋巴瘤的克隆造血：淋巴瘤和治疗相关骨髓肿瘤的临床影响和遗传相关性。

• 发表时间: 2023-03-01
• 影响因子: 10.1
• 作者: Liu, Ying;Derkach, Andriy;Lewis, Natasha;Zhu, Menglei;Zhang, Yanming;Arcila, Maria;Salles, Gilles;Dogan, Ahmet;Xiao, Wenbin
• 通讯作者: Xiao, Wenbin

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms.

世界卫生组织血淋巴肿瘤分类第五版：淋巴肿瘤。

• 发表时间: 2022-07
• 影响因子: 11.4
• 作者: Alaggio, Rita;Amador, Catalina;Anagnostopoulos, Ioannis;Attygalle, Ayoma D;Araujo, Iguaracyra Barreto de Oliveira;Berti, Emilio;Bhagat, Govind;Borges, Anita Maria;Boyer, Daniel;Calaminici, Mariarita;Chadburn, Amy;Chan, John K C;Cheuk, Wah;Chn
• 通讯作者: Chn

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms.

世界卫生组织血淋巴肿瘤分类第五版：骨髓和组织细胞/树突状肿瘤。

• 发表时间: 2022-07
• 影响因子: 11.4
• 作者: Khoury, Joseph D;Solary, Eric;Abla, Oussama;Akkari, Yassmine;Alaggio, Rita;Apperley, Jane F;Bejar, Rafael;Berti, Emilio;Busque, Lambert;Chan, John K C;Chen, Weina;Chen, Xueyan;Chng, Wee;Choi, John K;Colmenero, Isabel;Coupland, Sarah E
• 通讯作者: Coupland, Sarah E