Role of ASXL1 in normal and abnormal granulopoiesis.

项目总结 ASXL1是一种表观遗传调节蛋白，在骨髓增生异常中经常突变 综合征和骨髓增生性肿瘤。ASXL1的突变与 治疗耐药，预后差。ASXL1突变在CSF3R中高度丰富- 突变型骨髓增殖性肿瘤，以产生更多的 中性粒细胞。尽管ASXL1突变的频率很高，并与不良相关 预后，ASXL1在正常或异常中性粒细胞中的作用鲜为人知 制作。通过单细胞RNA测序，我们确定了ASXL1在 中性粒细胞发育正常。在这方面，ASXL1的缺失扰乱了RNA聚合酶II 功能并激活中性粒细胞祖细胞群体中的Myc信号网络。目标是 这项建议的目的是确定ASXL1控制中性粒细胞的分子机制 发展计划，并了解ASXL1截断突变如何有助于 骨髓增生性疾病生物学。我们的长期目标是利用这一机制 对开发逆转中性粒细胞缺陷的治疗干预措施的理解 与ASXL1突变相关的发展。

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.