Role of ASXL1 in normal and abnormal granulopoiesis.

ASXL1 在正常和异常粒细胞生成中的作用。

• 批准号: 10180659
• 负责人: Julia E Maxson
• 金额: $ 47.98万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10180659
• 关键词: Abnormal Neutrophil; Behavior; Biochemical; Biogenesis; Biology; Bone Marrow; CSF3R gene; Cells; Complex; Data; Defect; Development; Disease; Disease Progression; Dysmyelopoietic Syndromes; Elements; Epigenetic Process; Failure; Frequencies; Functional disorder; Gene Activation; Gene Expression; Genetic Transcription; Goals; Granulopoiesis; Hematopoiesis; High Prevalence; Histones; Impairment; Intervention; Knock-in Mouse; Knockout Mice; Molecular; Mutate; Mutation; Myelogenous; Myeloid Cells; Myeloproliferative disease; Outcome; Patient-Focused Outcomes; Patients; Phenotype; Play; Population; Process; Production; Prognosis; RNA Polymerase II; Recurrence; Regulation; Research; Role; Signal Transduction; Specific qualifier value; Study models; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transcription Initiation; Wild Type Mouse; base; design; genetic regulatory protein; granulocyte; improved; mutant; mutant mouse model; neutrophil; novel; peripheral blood; progenitor; prognostic significance; programs; promoter; single-cell RNA sequencing; therapy resistant; transcriptomics

PROJECT SUMMARY ASXL1 is an epigenetic regulatory protein that is frequently mutated in myelodysplastic syndromes and myeloproliferative neoplasms. Mutations in ASXL1 are associated with treatment resistance and poor prognosis. ASXL1 mutations are highly enriched in CSF3R- mutant myeloproliferative neoplasms, disorders characterized by an increased production of neutrophils. Despite the high frequency of ASXL1 mutations and association with poor prognosis, there is little known about the function of ASXL1 in normal or abnormal neutrophil production. Through single cell RNA sequencing, we identified an essential role for ASXL1 in normal neutrophil development. In this context, deletion of ASXL1 perturbs RNA polymerase II function and activates a Myc signaling network in the neutrophil progenitor population. The goal of this proposal is to define the molecular mechanisms by which ASXL1 controls the neutrophil developmental program, and to understand how truncating mutations in ASXL1 contribute to the biology of myeloproliferative disorders. Our long-term objective is to use this mechanistic understanding to develop therapeutic interventions that reverse the defects in neutrophil development associated with ASXL1 mutations.

项目总结