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 shortterm 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.

Identification of Oncostatin M as a STAT5-Dependent Mediator of Bone Marrow Remodeling in KIT D816V-Positive Systemic Mastocytosis

“…30 It has also been reported that OSM is expressed in murine erythroblasts and supports survival of erythroid progenitors in mice under anemic conditions. 47 In the present study, however, we did not detect expression of OSM in erythroid progenitors in human bone marrow. This finding was somewhat unexpected, but fits with the observation that human erythroid progenitors also did not express phosphorylated STAT5.…”

“…The most likely explanation for this discrepancy is that phosphorylated STAT5 and OSM are not expressed in steady-state hematopoiesis but only under anemic conditions, as has been reported for phenylhydrazine-induced anemia in mice. 47 The majority of patients with systemic mastocytosis harbor the KIT mutation D816V. In this study, we found that a KIT D816V Ϫ clone of the HMC-1 cell line displayed significantly lower OSM expression levels than KIT D816V ϩ HMC-1 cells.…”

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

“…Associated with these transcription pathways are the mitogen-activated protein kinases, which include the extracellular signal-related kinases (ERKs), the c-Jun-amino terminal kinases, and p38 MAP kinase, which can oversee erythroid proliferation and differentiation (Nagata et al, 1998). Yet, in regard to cytoprotection, EPO has been shown to not only activate STAT 3 (Asaumi et al, 2007;Parsa et al, 2003), STAT 5 Menon et al, 2006b;Moon et al, 2006;Um and Lodish, 2006;Wei et al, 2006), and ERK 1/2 (Bullard et al, 2005;Menon et al, 2006a), but also to employ these pathways for cell development and cell protection (Figure 2). For example, EPO significantly activates STAT3, STAT5, and ERK 1/2 in primary cerebral vascular cells, suggesting that EPO may require these cellular pathways to confer EC cytoprotection during oxidative stress (Table 2).…”

Erythropoietin and Oxidative Stress

“…However, in regards to cytoprotection, EPO has been shown to not only activate STAT 3 (Asaumi, et al, 2007, Parsa, et al, 2003, STAT 5 (Chong and Maiese, 2007a, Menon, et al, 2006b, Moon, et al, 2006, Um and Lodish, 2006, Wei, et al, 2006, and ERK 1/2 (Bullard, et al, 2005, Menon, et al, 2006a, but also to employ these pathways for cell development and cell protection. EPO activates STAT3, STAT5, and ERK 1/2 in primary cerebral vascular cells, suggesting that EPO may require these cellular pathways to confer EC cytoprotection during oxidative stress .…”