Defining the Synergistic Role of NPM1 and DNMT3A Mutations on HOX Gene Regulation in the Pathogenesis of Acute Myeloid Leukemia

确定 NPM1 和 DNMT3A 突变对 HOX 基因调控在急性髓系白血病发病机制中的协同作用

• 批准号: 10536092
• 负责人: Gandhar Kiran Datar
• 金额: $ 4.71万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536092
• 关键词: Acetylation; Acute Myelocytic Leukemia; Adult; Adult Acute Myeloblastic Leukemia; Animals; Binding; Biogenesis; Biological Assay; Bone Marrow; Cell Line; ChIP-seq; Chromatin; Chromatin Structure; Complex; DNA; DNA Modification Methylases; DNMT3a; DNMT3a mutation; Data; Development; Diagnosis; Epigenetic Process; Feedback; Fluorescent in Situ Hybridization; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Global Change; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic stem cells; Heterochromatin; Histones; Homeobox Genes; Immunofluorescence Immunologic; In Vitro; Individual; Knock-out; Lead; Leukemic Cell; Ligation; Maintenance; Malignant Neoplasms; Mediating; Methylation; Molecular; Mus; Mutate; Mutation; Myelogenous; Nuclear; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Prognosis; Proteins; Publishing; Regulation; Reporting; Ribosomes; Role; Somatic Mutation; Testing; Transposase; Undifferentiated; United States; Update; Variant; Work; acute myeloid leukemia cell; chromatin immunoprecipitation; epigenetic regulation; experimental study; genomic locus; high risk; histone modification; improved; in vivo; insight; leukemia; leukemogenesis; mouse model; mutant; novel therapeutics; nucleophosmin; prevent; protein protein interaction; relapse risk; response; synergism; targeted treatment

Project Summary/Abstract The overarching goal of this proposal is to determine how mutations in Nucleophosmin 1 (NPM1) and DNA Methyltransferase 3A (DNMT3A) cooperatively regulate HOX gene expression in the development of acute myeloid leukemia (AML). AML is a hematological malignancy arising from somatic mutations in hematopoietic progenitor cells that lead to their expansion in the bone marrow niche. Approximately 20,000 cases of AML are diagnosed annually in the United States, with a 5-year survival of less than 30%. NPM1 and DNMT3A are the most frequently mutated genes in AML, occurring in 30% and 20% of all cases, respectively. These mutations frequently co-occur, with nearly 70% of NPM1-mutant AML harboring a concomitant DNMT3A mutation. Together, these mutations confer a worse overall prognosis. Despite their established association, the synergistic mechanisms that drive robust malignancy in the presence of both NPM1/DNMT3A mutations are poorly understood, thus preventing the development of effective targeted therapies. Our group and others have shown that these mutations converge on HOX regulation, where high HOX expression maintains leukemic cells in an undifferentiated state. Our group has shown that mutant NPM1 is required for HOX expression in AML. Moreover, DNMT3A mutations have been associated with global changes in methylation, particularly at HOX loci. To better define the mechanism of mutant NPM1, I performed a protein interaction screen that revealed mutant NPM1 interacts with the rixosome, a conserved ribosomal biogenesis complex with additional roles in HOX gene silencing. We hypothesize that, during AML pathogenesis, DNMT3A mutations enhance chromatin accessibility at HOX gene loci, which robustly increases the ability of mutant NPM1 to interfere with rixosome-mediated HOX gene silencing. To test this hypothesis, we will first determine the mechanism of increased HOX expression by mutant NPM1, with specific focus on the rixosome’s role in HOX gene silencing. We will also characterize HOX chromatin organization in NPM1/DNMT3A mutant AML in vitro and in vivo. This proposed work will reveal key molecular mechanisms underlying the most common co-mutations found in AML. As a result, these studies will identify new therapeutic vulnerabilities in NPM1/DNMT3A mutant AML and clear a path for the development of targeted therapies to improve patient outcomes.

项目总结/文摘