Signals for stress erythropoiesis are integrated via an erythropoietin receptor–phosphotyrosine-343–Stat5 axis
Madhu P. Menon, Vinit Karur, Olga Bogacheva, Oleg Bogachev, Bethany Cuetara, Don M. Wojchowski
Madhu P. Menon, Vinit Karur, Olga Bogacheva, Oleg Bogachev, Bethany Cuetara, Don M. Wojchowski
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Research Article Hematology

Signals for stress erythropoiesis are integrated via an erythropoietin receptor–phosphotyrosine-343–Stat5 axis

Abstract

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.

Authors

Madhu P. Menon, Vinit Karur, Olga Bogacheva, Oleg Bogachev, Bethany Cuetara, Don M. Wojchowski

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Aberrant splenic architecture and CFUe and BFUe formation in phenylhydra...
Aberrant splenic architecture and CFUe and BFUe formation in phenylhydrazine-treated EpoR-HM mice, and rescue of extramedullary erythropoiesis by EpoR-H. (A) At day 4 after phenylhydrazine treatment, spleens from EpoR-HM, EpoR-H, and WT-EpoR mice were fixed, sectioned, stained (H&E), and examined for white and red pulp architecture. Histomorphologies are representative of 4 mice per group (and 20 sections per mouse) and are presented at ×40 magnification. Also illustrated are EpoR-HM–specific deficiencies in splenomegaly. (B) EpoR-HM–specific defects in splenic Ter119+ erythroblast formation and Epo-dependent proliferation, and rescue by EpoR-H. Frequencies of Ter119+ erythroblasts in splenocyte preparations from phenylhydrazine-treated WT-EpoR, EpoR-HM, and EpoR-H mice are shown. Also graphed are rates of Epo-induced 3HdT incorporation for splenic erythroid progenitor cells (prepared at day 3). (C) At day 2 after phenylhydrazine treatment, frequencies of splenic CFUe and BFUe were determined. For each analysis, mean values ± SEM are illustrated (n = 3 mice per group). Results are representative of 3 independent experiments.