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.