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.

项目总结/摘要 RUNT相关转录因子1（RUNX 1）是造血和白血病发生的主要调节因子。 在10-20%的急性髓性白血病（AML）患者中发现了RUNX 1突变。RUNX 1突变体 AML的特点是化疗耐药性和预后差。血统不忠在RUNX 1突变体中普遍存在 AML和已被提出作为一个潜在的机制，治疗耐药。然而，机制 RUNX 1突变在AML中赋予谱系不忠实性，以及谱系不忠实性对AML的特异性贡献。 RUNX 1突变型AML的发病机制仍然知之甚少。致白血病RUNX 1突变可能 在白血病发生和谱系特化中具有潜在的MUR特异性功能。NRAS突变 是表现出谱系不忠的RUNX 1突变型AML中最常见的共突变基因，这表明 NRAS突变与致病性RUNX 1突变协同促进白血病发生和谱系 不忠当前的临床前模型，包括诱导型Runx 1缺失小鼠和种系Runx 1 R174 Q突变 并不适合检验这一假设在这项提议中，我们将利用一种新的诱导性，可逆的 Runx 1 R174 Q等位基因，单独或与协同Nras疾病等位基因一起。这将使我们能够描述 RUNX 1的突变特异性功能，突变对白血病转化和谱系的影响 不忠，并解决白血病的启动和维持中RUNX 1突变的要求。的 本项目的具体目标是：1）描述血统不忠，遗传异质性及其预后 RUNX 1突变型AML的相关性。2)确定Runx 1 R174 Q和Runx 1 R174 Q + NrasG 12 D诱导白血病发生和谱系不忠实。3)研究Runx 1 R174 Q突变在 疾病的发生和维持。这些研究将有助于更好地了解疾病机制 和新的治疗模式，这也将塑造我未来独立实验室的重点。 肖文斌，医学博士，博士，MSKCC的助理成员，将进行这个项目作为4年职业生涯的一部分 他制定了发展计划，将75%的时间用于研究，其余时间用于临床工作。文斌是 由Ross Levine博士指导，他是世界血液恶性肿瘤专家。他还得到了奥马尔博士的建议 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。 药他将与生物系的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， 具有双重重组酶的白血病小鼠模型，表观遗传调控方面的知识，以及 生物信息学在短期内，该项目的目标是发表两篇关于这项研究结果的论文。在 从长远来看，目标是制定一个研究计划，并获得R 01资金，成为一个 血液恶性肿瘤的独立实验室研究者。

项目成果

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

• DOI: 10.1038/s41375-022-01613-1
• 发表时间: 2022-07
• 期刊: LEUKEMIA
• 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-Joo;Choi, John K.;Colmenero, Isabel;Coupland, Sarah E.;Cross, Nicholas C. P.;De Jong, Daphne;Elghetany, M. Tarek;Takahashi, Emiko;Emile, Jean-Francois;Ferry, Judith;Fogelstrand, Linda;Fontenay, Michaela;Germing, Ulrich;Gujral, Sumeet;Haferlach, Torsten;Harrison, Claire;Hodge, Jennelle C.;Hu, Shimin;Jansen, Joop H.;Kanagal-Shamanna, Rashmi;Kantarjian, Hagop M.;Kratz, Christian P.;Li, Xiao-Qiu;Lim, Megan S.;Loeb, Keith;Loghavi, Sanam;Marcogliese, Andrea;Meshinchi, Soheil;Michaels, Phillip;Naresh, Kikkeri N.;Natkunam, Yasodha;Nejati, Reza;Ott, German;Padron, Eric;Patel, Keyur P.;Patkar, Nikhil;Picarsic, Jennifer;Platzbecker, Uwe;Roberts, Irene;Schuh, Anna;Sewell, William;Siebert, Reiner;Tembhare, Prashant;Tyner, Jeffrey;Verstovsek, Srdan;Wang, Wei;Wood, Brent;Xiao, Wenbin;Yeung, Cecilia;Hochhaus, Andreas
• 通讯作者: Hochhaus, Andreas

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

• DOI: 10.1038/s41375-022-01620-2
• 发表时间: 2022-07
• 期刊: LEUKEMIA
• 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;Chng, Wee-Joo;Choi, John K.;Chuang, Shih-Sung;Coupland, Sarah E.;Czader, Magdalena;Dave, Sandeep S.;de Jong, Daphne;Du, Ming-Qing;Elenitoba-Johnson, Kojo S.;Ferry, Judith;Geyer, Julia;Gratzinger, Dita;Guitart, Joan;Gujral, Sumeet;Harris, Marian;Harrison, Christine J.;Hartmann, Sylvia;Hochhaus, Andreas;Jansen, Patty M.;Karube, Kennosuke;Kempf, Werner;Khoury, Joseph;Kimura, Hiroshi;Klapper, Wolfram;Kovach, Alexandra E.;Kumar, Shaji;Lazar, Alexander J.;Lazzi, Stefano;Leoncini, Lorenzo;Leung, Nelson;Leventaki, Vasiliki;Li, Xiao-Qiu;Lim, Megan S.;Liu, Wei-Ping;Louissaint, Abner, Jr.;Marcogliese, Andrea;Medeiros, L. Jeffrey;Michal, Michael;Miranda, Roberto N.;Mitteldorf, Christina;Montes-Moreno, Santiago;Morice, William;Nardi, Valentina;Naresh, Kikkeri N.;Natkunam, Yasodha;Ng, Siok-Bian;Oschlies, Ilske;Ott, German;Parrens, Marie;Pulitzer, Melissa;Rajkumar, S. Vincent;Rawstron, Andrew C.;Rech, Karen;Rosenwald, Andreas;Said, Jonathan;Sarkozy, Clementine;Sayed, Shahin;Saygin, Caner;Schuh, Anna;Sewell, William;Siebert, Reiner;Sohani, Aliyah R.;Tooze, Reuben;Traverse-Glehen, Alexandra;Vega, Francisco;Vergier, Beatrice;Wechalekar, Ashutosh D.;Wood, Brent;Xerri, Luc;Xiao, Wenbin
• 通讯作者: Xiao, Wenbin