The role of NPM1 in preserving a hematopoietic stem cell identity

NPM1 在保持造血干细胞身份中的作用

• 批准号: 10641005
• 负责人: Thelma Escobar
• 金额: $ 20.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-08 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641005
• 关键词: Acute Myelocytic Leukemia; Adult; Adult Acute Myeloblastic Leukemia; Affinity Chromatography; Applications Grants; Auxins; Biogenesis; Biology; Cell Cycle; Cell Differentiation process; Cell Lineage; Cells; Child; Chromatin; Complement; Cre-LoxP; Data; Defect; Degradation Pathway; Deposition; Development; Diagnosis; Disease; Embryo; Embryonic Development; Epigenetic Process; Equilibrium; Essential Genes; Etiology; Gene Mutation; Generations; Genes; Genetic Transcription; Genome Stability; Goals; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Heritability; Histones; Human; In Vitro; Inherited; Investigation; Knockout Mice; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Molecular; Molecular Chaperones; Mus; Mutate; Mutation; Neurons; Nuclear Family; Nucleosomes; Organogenesis; Pathogenesis; Patients; Phenotype; Plant Growth Regulators; Plants; Play; Polyubiquitination; Postdoctoral Fellow; Process; Protein Isoforms; Proteins; Recycling; Repression; Research; Ribosomes; Role; Seminal; Shapes; Specific qualifier value; Stem Cell Development; System; Technology; Transcript; Transgenic Mice; United States; chromatin remodeling; de novo mutation; design; driver mutation; embryonic stem cell; epigenome; genome-wide; hematopoietic differentiation; hematopoietic stem cell differentiation; hematopoietic stem cell fate; improved; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; insight; interest; leukemia; mouse model; multicatalytic endopeptidase complex; mutant; nucleophosmin; nucleoplasmin; preservation; programs; protein function; receptor binding; self-renewal; stem cell function; targeted treatment

NPM1 gene mutations are considered driver mutations in the pathogenesis of acute myeloid leukemia (AML). Nucleophosmin (NPM1) belongs to the nucleophosmin/nucleoplasmin (NPM) family of nuclear chaperones, of which there are three genes: NPM1, NPM2 (nucleoplasmin), and NPM3, whose protein functions include chromatin remodeling, genome stability, ribosome biogenesis, and embryogenesis. In humans, NPM1 has three isoforms of which isoform 1 is the predominant type and is the only one expressed in mouse. My postdoctoral studies focused on a fundamental epigenetic feature involving the local recycling of parental nucleosomes, which showed that repressed, but not active, chromatin domains are inherited. While attempting to identify a histone chaperone(s) that facilitates the inheritance of repressed chromatin domains in mouse embryonic stem cells (mESCs), I discovered that NPM1 plays an essential role in this process (preliminary data). While the role of NPM1 in the cell has been well characterized, its function in normal hematopoiesis remains unknown. With regard to hematopoietic stem cells (HSCs), the epigenome confers self-renewal and differentiation functions wherein inheritance of HSC chromatin states is persistent across cell cycles. In this proposal, we will identify the molecular basis of NPM1 in constructing the heritable epigenome of HSCs and determine whether aberrant function in this process contributes to the etiology of NPM1-driven cancer mutations. As species- specific differences exist between mouse and human NPM1 biology, we propose to complement human and mouse NPM1 biology utilizing in vitro human and in vivo mouse HSC differentiation systems. These systems include in vitro human induced Pluripotent Stem Cells (iPSCs) to differentiate and derive a hematopoietic progenitor cell (HPC) fate and developing an Auxin-induced degron (AID) mouse model for NPM1 to deplete NPM1 protein in vivo in a targeted and regulated manner in HSCs. Integrating human iPSC technology with an AID mouse model for NPM1 has the potential to set a precedent in assessing the function of essential genes that are frequently mutated in disease. In this instance, identifying NPM1 mediated chromatin mechanisms necessary for constructing the heritable epigenome of HSCs and its aberrant function in leukemia.

NPM1基因突变被认为是急性髓性白血病（AML）发病机制中的驱动突变。