Epo-IGF1R cross talk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm
Year: 2022
Type: article
Abstract: We found that in regenerative erythropoiesis, the erythroid progenitor landscape is reshaped, and a previously undescribed progenitor population with colony-forming unit-erythroid (CFU-E) activity (stress CFU-E [sCFU-E]) is expanded markedly to restore the erythron. sCFU-E cells are targets of erythropoietin (Epo), and sCFU-E expansion requires signaling from the Epo receptor (EpoR) cytoplasmic tyrosines. Molecularly, Epo promotes sCFU-E expansion via JAK2- and STAT5-dependent expression of IRS2, thus engaging the progrowth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R and IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR-lacking cytoplasmic tyrosines. This sCFU-E pathway is the major pathway involved in erythrocytosis driven by the oncogenic JAK2 mutant JAK2(V617F) in myeloproliferative neoplasm. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis. In samples from patients with myeloproliferative neoplasm, the number of sCFU-E-like cells increases, and inhibition of IGR1R and IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. In summary, we identified a new stress-specific erythroid progenitor cell population that links regenerative erythropoiesis to pathogenic erythrocytosis.
Source: Blood
Authors: Hsi-Hsien Hsieh, Huiyu Yao, Yue Ma, Yuannyu Zhang, Xue Xiao, Helen Stephens, Naureen Wajahat, Stephen S. Chung, Lin Xu, Jian Xu, Raajit K. Rampal, Lily Jun-shen Huang
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Rally Foundation, Cancer Prevention and Research Institute of Texas, Memorial Sloan-Kettering Cancer Center, Incyte, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1016636649, Recruitment of First-Time, Tenure-Track Faculty Members, G1818054408, G2325851841, G2458514892, G2878433095, G289723095, G4223759923, Identifying neuroblastoma drivers and bringing them to the clinic, G69123555, Pediatric Cancer Data Core, Targeting Metabolic Liabilities of Leukemia-Initiating Cells (R01CA230631), G803893432, Targeting Twist2 Pathway as a Potential Therapy of Rhabdomvosarcoma, Cancer Center Support Grant, UT Southwestern Medical Center Simmons Comprehensive Cancer Center, Molecular Analysis of Transcriptional Enhancers in Hematopoiesis, Erythropoietin receptor signaling in stress erythropoiesis and erythrocytosis
OpenAlex ID: W4294335566