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Principal Investigator: Diane S Krause
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $669,741
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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Abstract
Fate specification is a fundamental aspect of hematopoietic stem and progenitor cell biology. The proposed studies are focused on the still elusive molecular mechanisms that direct bipotent megakaryocyte-erythroid progenitors (MEP) towards downstream unipotent megakaryocytic progenitors (MkP) and erythroid progenitors (ErP), which are essential for platelet and red blood cell production. Building on our published studies and new preliminary data, we will test how the transcription factor RUNX1, one of the most commonly mutated genes in acute myeloid leukemia, regulates MEP fate. In collaboration with experts in proteomics, and transcriptional initiation we will use state-of-the-art approaches to test the hypothesis that phosphorylation of specific serines and threonines of RUNX1 by CDK9 and other kinases promotes the transcriptional elongation of genes that promote the megakaryocytic fate whereas inhibition of this phosphorylation promotes the erythroid fate. Sorted MEP, MkP and ErP populations provide a unique opportunity to study mechanisms of fate specification as they are extremely close to one another developmentally, yet have distinctly different differentiation potential. Using cell and molecular biology along with highly innovative proteomics approaches, we will 1) determine the differential levels of phospho-RUNX1 proteoforms in primary MEP, MkP, and ErP; 2) test the degree to which the upstream kinase CDK9 promotes RUNX1 Serine and Threonine phosphorylation; and 3) assess potential downstream mechanisms by which phosphorylated RUNX1 regulates MEP fate specification. This research holds significant promise for advancing our understanding of hematopoiesis and has implications for therapeutic interventions in Hematology and Transfusion Medicine as well as broad implications regarding fundamental mechanisms in fate specification.
Terms: <AML - Acute Myeloid Leukemia><AML1><AMLCR1><ATAC><ATAC sequencing><ATAC-seq><ATACseq><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Address><Affect><Assay for Transposase-Accessible Chromatin using sequencing><Basal Transcription Factor><Basal transcription factor genes><Binding><Blood Diseases><Blood Platelets><Blood Precursor Cell><Blood erythrocyte><Blood megakaryocyte><Bone Marrow><Bone Marrow Reticuloendothelial System><CBFA2><CDK9 Kinase><CDK9 Protein Kinase><CUT&RUN><Cdc2-related Kinase PITALRE><Cell Body><Cells><Cellular biology><Chromatin><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Collaborations><Cyclin-Dependent Kinase 9><DNA Molecular Biology><Data><Detection><Development><ERYF1><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Erythrocytes><Erythrocytic><Erythroid><Erythroid Precursor Cells><Erythroid Progenitor Cells><Erythroid Stem Cells><Erythropoietic Progenitor Cells><Erythropoietic Stem Cells><GATA Binding Protein 1><GATA-1><GATA1><GATA1 gene><GATA1 protein><GATA1 transcription factor><GF-1 protein><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Hematologic Diseases><Hematological Disease><Hematological Disorder><Hematology><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Human><Kinases><Knowledge><L-Serine><L-Threonine><LPTN><Maps><Marrow erythrocyte><Marrow platelet><Mediating><Megakaryocytes><Megakaryocytopoieses><Megakaryopoiesis><Megalokaryocyte><Modern Man><Molecular><Molecular Biology><Molecular Interaction><Mutate><NF-E1 erythroid-specific transcription factor><NFE1 protein><Non-Polyadenylated RNA><PEBP2A2><PEBP2aB><PITALRE Kinase><Phosphorylation><Phosphorylation Inhibition><Phosphorylation Site><Phosphorylserine><Phosphoserine><Phosphotransferase Gene><Phosphotransferases><Platelets><Production><Productivity><Progenitor Cells><Protein Phosphorylation><Proteomics><Publishing><RNA><RNA Expression><RNA Gene Products><RUNX1><RUNX1 gene><Recommendation><Red Blood Cells><Red Cell><Regulation><Research><Ribonucleic Acid><SCM-1><SCM-1a><SCM1><SCYC1><Serine><Serine Phosphate><Serine/Threonine Phosphorylation><Seryl Phosphate><Sorting><Specific qualifier value><Specified><Technology><Testing><Text><Therapeutic Intervention><Threonine><Thrombocytes><Transcription><Transcription Elongation><Transcription Factor GATA1><Transcription Factor Proto-Oncogene><Transcription Initiation><Transcription factor genes><Transphosphorylases><XCL1><XCL1 gene><acute granulocytic leukemia><acute myeloid leukemia><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><blood cell formation><blood cell progenitor><blood corpuscles><blood disorder><blood progenitor><blood stem cell><blood treatment><blood-forming stem cell><cell biology><cell type><clinical applicability><clinical application><developmental><differential expression><differentially expressed><epigenetically><globin transcription factor 1><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><human progenitor><human stem cells><innovate><innovation><innovative><intervention therapy><knock-down><knockdown><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nuclear factor-erythroid 1><progenitor><progenitor biology><progenitor cell biology><progenitor cell fate><progenitor cell fate specification><progenitor cell population><progenitor fate><progenitor fate specification><progenitor population><progenitor specification><promoter><promotor><stem and progenitor biology><stem and progenitor cell fate><stem and progenitor cell population><stem cell biology><stem cell fate><stem cell fate specification><stem cell population><stem cell specification><stem cells><transcription factor><transcription factor NFE-1><transcriptional differences><transfusion medicine><upstream kinase>