Signals for stress erythropoiesis are integrated via an erythropoietin receptor-phosphotyrosine-343-Stat5 axis.
Anemia due to chronic disease or chemotherapy often is ameliorated by erythropoietin (Epo). Present studies reveal that, unlike steady-state erythropoiesis, erythropoiesis during anemia depends sharply on an Epo receptor-phosphotyrosine-343-Stat5 signaling axis. In mice expressing a phosphotyrosine-null (PY-null) Epo receptor allele (EpoR-HM), severe and persistent anemia was induced by hemolysis or 5-fluorouracil. In short-term transplantation experiments, donor EpoR-HM bone marrow cells also failed to efficiently repopulate the erythroid compartment. In each context, stress erythropoiesis was rescued to WT levels upon the selective restoration of an EpoR PY343 Stat5-binding site (EpoR-H allele). As studied using a unique primary culture system, EpoR-HM erythroblasts exhibited marked stage-specific losses in Epo-dependent growth and survival. EpoR-H PY343 signals restored efficient erythroblast expansion, and the selective Epo induction of the Stat5 target genes proviral integration site-1 (Pim-1) and oncostatin-M. Bcl2-like 1 (Bcl-x), in contrast, was not significantly induced via WT-EpoR, EpoR-HM, or EpoR-H alleles. In Kit+ CD71+ erythroblasts, EpoR-PY343 signals furthermore enhanced SCF growth effects, and SCF modulation of Pim-1 kinase and oncostatin-M expression. In maturing Kit- CD71+ erythroblasts, oncostatin-M exerted antiapoptotic effects that likewise depended on EpoR PY343-mediated events. Stress erythropoiesis, therefore, requires stage-specific EpoR-PY343-Stat5 signals, some of which selectively bolster SCF and oncostatin-M action.
Menon
Madhu P
MP
Stem and Progenitor Cell Biology Program, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA.
Karur
Vinit
V
Bogacheva
Olga
O
Bogachev
Oleg
O
Cuetara
Bethany
B
Wojchowski
Don M
DM
D000740:Anemia / Q000097:blood / Q000139:chemically induced / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004900:Erythroblasts / Q000166:cytology; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010659:Phenylhydrazines / Q000008:administration & dosage; D019000:Phosphotyrosine / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D010659:Phenylhydrazines; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; C030299:phenylhydrazine; D019000:Phosphotyrosine; D019009:Proto-Oncogene Proteins c-kit