Epo-IGF1R cross talk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm Journal Article
| Authors: | Hsieh, H. H.; Yao, H.; Ma, Y.; Zhang, Y.; Xiao, X.; Stephens, H.; Wajahat, N.; Chung, S. S.; Xu, L.; Xu, J.; Rampal, R. K.; Huang, L. J. S. |
| Article Title: | Epo-IGF1R cross talk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm |
| 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. © 2022 The American Society of Hematology |
| Keywords: | signal transduction; adult; controlled study; myeloproliferative disorders; human cell; genetics; myeloproliferative disorder; hydroxyurea; janus kinase 2; nonhuman; drug megadose; mutant protein; neoplasm; neoplasms; mouse; metabolism; low drug dose; apoptosis; gene expression; erythropoietin; phenylhydrazine; cell growth; erythroblast; erythroid precursor cell; erythropoiesis; erythroid precursor cells; animal experiment; dexamethasone; in vitro study; cell population; tyrosine; transcriptomics; physiology; somatomedin c receptor; receptor, igf type 1; polycythemia; splenomegaly; endoglin; cytoplasm; stat5 protein; transcriptome; recombinant erythropoietin; erythropoietin receptor; myeloproliferative neoplasm; cell stress; stem cell expansion; erythrocyte count; colony formation; insulin receptor substrate 2; phlebotomy; cd150 antigen; granulocytosis; burst forming unit e; erythrocytosis; cd71 antigen; decay accelerating factor; receptors, erythropoietin; humans; human; article; rna sequencing; colony forming unit e; differential gene expression; jak-stat signaling; igf1r protein, human |
| Journal Title: | Blood |
| Volume: | 140 |
| Issue: | 22 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2022-12-01 |
| Start Page: | 2371 |
| End Page: | 2384 |
| Language: | English |
| DOI: | 10.1182/blood.2022016741 |
| PUBMED: | 36054916 |
| PROVIDER: | scopus |
| PMCID: | PMC9837451 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 January 2023 -- Source: Scopus |
