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Blood, 15 January 2005, Vol. 105, No. 2, pp. 552-561.
Prepublished online as a Blood First Edition Paper on June 22, 2004; DOI 10.1182/blood-2003-09-3237.
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Submitted September 24, 2003
Accepted May 21, 2004
A Novel Role for STAT1 in Regulating Murine Erythropoiesis: Deletion of STAT1 Results in Overall Reduction of Erythroid Progenitors and Alters Their Distribution
Adrienne Halupa, Monica Bailey, Kai Huang, Norman N Iscove, David E Levy, and Dwayne L Barber*
Departments of Medical Biophysics, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Division of Cellular and Molecular Biology, Ontario Cancer Institute, Toronto, Ontario, Canada
Division of Cellular and Molecular Biology, Ontario Cancer Institute, Toronto, Ontario, Canada
Department of Pathology, New York University, New York, NY, USA
Departments of Medical Biophysics, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Division of Cellular and Molecular Biology, Ontario Cancer Institute, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada
* Corresponding author; email: dbarber{at}uhnres.utoronto.ca.
Erythropoietin (EPO) activates many distinct signal transduction cascades upon engagement of its receptor. Deletion of the erythropoietin, erythropoietin receptor (EPO-R) or JAK2 genes in mice results in embryonic lethality due to a fatal anemia. EPO activates STAT1, STAT3 and STAT5a/b transcription factors in erythroid cell lines. Studies have focused on STAT5 as the primary target of EPO-dependent JAK2 activation. However, STAT5a/b-/- mice are viable, displaying a non-fatal anemia during embryogenesis, and delayed differentiation in adult erythropoiesis. Importantly, EPO-R cytoplasmic tyrosines are dispensable for viability in vivo. Interestingly, no cytoplasmic tyrosines are required for phosphorylation of STAT1. This led us to examine whether STAT1-deficient mice have altered erythropoiesis. A shift in erythropoiesis was observed in STAT1-/- mice, with reduced bone marrow-derived CFU-E and a compensatory increase in splenic BFU-E and CFU-E. Both types of splenic-derived cells displayed EPO hyperresponsiveness. A 1.6-fold reduction in total CFU-E was observed in STAT1-deficient mice, whereas total BFU-E were comparable. Flow cytometry of STAT1-deficient erythroid cells revealed a less differentiated phenotype, associated with increased apoptosis of early erythroblasts. STAT1-deficient erythroblasts from phenylhydrazine-primed mice displayed enhanced phosphorylation of STAT5a/b, Erk1/2, and PKB/Akt. These results illustrate that STAT1 plays an important role in the regulation of erythropoiesis.
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