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: 10378101
• 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/10378101
• 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.

项目摘要 ASXL 1是一种表观遗传调节蛋白，在骨髓增生异常综合征中经常发生突变。 综合征和骨髓增生性肿瘤。ASXL 1的突变与 治疗抵抗和预后差。ASXL 1突变在CSF 3R中高度富集- 突变型骨髓增生性肿瘤，特征为 中性粒细胞尽管ASXL 1突变的频率很高， ASXL 1在正常或异常中性粒细胞中的功能尚不清楚， 生产通过单细胞RNA测序，我们确定了ASXL 1在 中性粒细胞发育正常。在这种情况下，ASXL 1的缺失扰乱RNA聚合酶II 在中性粒细胞祖细胞群中发挥功能并激活Myc信号网络。目标 这项提议的一个重要目的是确定ASXL 1控制中性粒细胞的分子机制， 发展计划，并了解如何截断突变ASXL 1有助于 骨髓增生性疾病的生物学。我们的长期目标是利用这一机制 了解开发治疗干预措施，逆转中性粒细胞 与ASXL 1突变相关的发展。