Role of ASXL1 in normal and abnormal granulopoiesis.

ASXL1 在正常和异常粒细胞生成中的作用。

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 ASXL1 是一种表观遗传调节蛋白，在骨髓增生异常中经常发生突变综合征和骨髓增生性肿瘤。 ASXL1 的突变与治疗抵抗和预后不良。 ASXL1 突变在 CSF3R 中高度富集突变型骨髓增生性肿瘤，以骨髓增殖性肿瘤的产生增加为特征的疾病中性粒细胞。尽管 ASXL1 突变频率很高并且与不良相关对于 ASXL1 在正常或异常中性粒细胞中的功能知之甚少生产。通过单细胞 RNA 测序，我们确定了 ASXL1 在中性粒细胞发育正常。在这种情况下，ASXL1 的缺失会扰乱 RNA 聚合酶 II 功能并激活中性粒细胞祖细胞群中的 Myc 信号网络。目标该提案的目的是定义 ASXL1 控制中性粒细胞的分子机制发育计划，并了解 ASXL1 的截短突变如何促进骨髓增殖性疾病的生物学。我们的长期目标是利用这种机制了解开发扭转中性粒细胞缺陷的治疗干预措施发育与 ASXL1 突变相关。