Role of ASXL1 in normal and abnormal granulopoiesis.

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Principal Investigator: Julia E Maxson
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2024
Award: $470,191
Funding agency: National Heart Lung and Blood Institute

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.

Terms: <Abnormal Neutrophil><Acceleration><Behavior><Biochemical><Biogenesis><Biology><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood granulocytic cell><Bone Marrow><Bone Marrow Reticuloendothelial System><CD114><CD114 Antigen><CSF3R><CSF3R gene><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Colony Stimulating Factor 3 Receptor><Complex><DNA-Dependent RNA Polymerase II><Data><Defect><Development><Disease><Disease Progression><Disorder><Dysfunction><Dysmyelopoietic Syndromes><Elements><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Failure><Frequencies><Functional disorder><G-CSF Receptors><GCSF Receptor><GCSFR><Gene Activation><Gene Expression><Gene Transcription><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><Granular Leukocytes><Granulocyte Colony-Stimulating Factor Receptors><Granulocytic cell><Granulopoiesis><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><High Prevalence><Histones><Impairment><Intervention><Intervention Strategies><Intracellular Communication and Signaling><KI mice><KO mice><Knock-in Mouse><Knock-out Mice><Knockout Mice><Marrow Neutrophil><Molecular><Mutate><Mutation><Myelodysplastic Disease><Myelodysplastic Syndromes><Myelodysplastic/Myeloproliferative Disease><Myelodysplastic/myeloproliferative neoplasm><Myelogenous><Myeloid><Myeloid Cells><Myeloid Disease><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><Myeloproliferative/Myelodysplastic Disorders><Myeloproliferative/Myelodysplastic Syndromes><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Null Mouse><Origin of Life><Outcome><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phenotype><Physiopathology><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Process><Production><Prognosis><RNA Expression><RNA Polymerase B><RNA Polymerase II><Recurrence><Recurrent><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><Regulation><Regulatory Protein><Research><Role><Signal Transduction><Signal Transduction Systems><Signaling><Smoldering Leukemia><Specific qualifier value><Specified><Study models><Techniques><Testing><Therapeutic><Therapeutic Intervention><Transcription><Transcription Initiation><Wild Type Mouse><biological signal transduction><blood cell formation><design><designing><developmental><epigenetically><genetic regulatory protein><genome mutation><granulocyte><improved><intervention therapy><interventional strategy><knockin mice><mutant><mutant mouse model><myelodysplasia><myeloproliferative neoplasm><neutrophil><novel><pathophysiology><patient oriented outcomes><peripheral blood><progenitor cell population><progenitor population><prognostic significance><programs><promoter><promotor><regulatory gene product><resistance to therapy><resistant to therapy><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem and progenitor cell population><stem cell population><therapeutic resistance><therapy resistant><transcriptomics><treatment resistance><wildtype mouse>