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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4511-4522.
Prepublished online as a Blood First Edition Paper on January 31, 2008; DOI 10.1182/blood-2007-07-102848.
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Submitted July 23, 2007
Accepted January 16, 2008
Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2
Florian Grebien, Marc A. Kerenyi, Boris Kovacic, Thomas Kolbe, Verena Becker, Helmut Dolznig, Klaus Pfeffer, Ursula Klingmuller, Mathias Muller, Hartmut Beug, Ernst W Mullner*, and Richard Moriggl
Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria
Research Institute of Molecular Pathology, Vienna, Austria
Dept. Agrobiotechnology, IFA-Tulln, Biotechnology in Animal Production, University of Natural Resources and Applied Life Sciences, Vienna, Austria
German Cancer Research Center, Heidelberg, Germany
Institute of Pathology, Medical University of Vienna, Vienna, Austria
Institute of Medical Microbiology, Heinrich-Heine University, Duesseldorf, Germany
Institute of Animal Breeding and Genetics, Veterinary University Vienna, Vienna, Austria
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
* Corresponding author; email: ernst.muellner{at}univie.ac.at.
Erythropoiesis requires erythropoietin (Epo) and stem cell factor (SCF) signaling via their receptors EpoR and c-Kit. EpoR – like many other receptors involved in hematopoiesis – acts via the kinase Jak2. Deletion of EpoR or Jak2 causes embryonic lethality due to defective erythropoiesis. The contribution of distinct EpoR/Jak2-induced signaling pathways (MAPK, PI3K, Stat5) to functional erythropoiesis is incompletely understood. Here we demonstrate that expression of a constitutively activated Stat5a mutant (cS5) was sufficient to relieve the proliferation defect of Jak2-/- and EpoR-/- cells in an Epo-independent manner. Also tamoxifen-induced DNA binding of a Stat5a-ER* fusion construct enabled erythropoiesis in the absence of Epo. Furthermore, c-Kit was able to enhance signaling through the Jak2-Stat5 axis, particularly in lymphoid and myeloid progenitors. Although abundance of hematopoietic stem cells was 2.5-fold reduced in Jak2-/- fetal livers, transplantation of Jak2-/--cS5 fetal liver cells into irradiated mice gave rise to mature erythroid and myeloid cells of donor origin up to 6 months after transplantation. Cytokine- and c-Kit pathways do not function independently of each other in hematopoiesis, but cooperate to attain full Jak2/Stat5 activation. In conclusion, activated Stat5 is a critical downstream effector of Jak2 in erythro-/myelopoiesis, and Jak2 functionally links cytokine- with c-Kit-receptor tyrosine kinase signaling.
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