1. ¹Institute of Molecular Pathology, Vienna Biocenter (VBC), Vienna, Austria
2. ²Max F. Perutz Laboratories, Department of Medical Biochemistry, Division of Molecular Biology, Medical University of Vienna, Vienna, Austria

Correspondence: Professor H Beug, Institute of Molecular Pathology Dr Bohr-Gasse 7, A-1030 Vienna, Austria. E-mail: beug@imp.univie.ac.at; Professor EW Müllner, Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Dr Bohr-Gasse 9, A-1030 Vienna, Austria. E-mail: ernst.muellner@univie.ac.at

³Present address: Institute of Clinical Pathology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.

⁴Present address: Department of Obstetrics and Gynecology, Division of Gynecological Endocrinology and Reproductive Medicine, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.

⁵Present address: Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstr.108, D-01307 Dresden, Germany.

⁶Present address: Gene Center, University of Munich, Feodor-Lynen Str. 25, D-81377 Munich, Germany.

⁷Present address: Ludwig Boltzmann Institute for Cancer Research, Währinger Strae 13A, A-1090, Vienna, Austria.

⁸These authors contributed equally to the work and should be regarded as joint first authors.

⁹These authors contributed equally to the work and should be regarded as senior co-authors.

Received 27 July 2005; Revised 2 November 2005; Accepted 3 November 2005; Published online 30 January 2006.

Abstract

The balance between hematopoietic progenitor commitment and self-renewal versus differentiation is controlled by various transcriptional regulators cooperating with cytokine receptors. Disruption of this balance is increasingly recognized as important in the development of leukemia, by causing enhanced renewal and differentiation arrest. We studied regulation of renewal versus differentiation in primary murine erythroid progenitors that require cooperation of erythropoietin receptor (EpoR), the receptor tyrosine kinase c-Kit and a transcriptional regulator (glucocorticoid receptor; GR) for sustained renewal. However, mice defective for GR- (GR^dim/dim), EpoR- (EpoR_H) or STAT5ab function (Stat5ab^–/–) show no severe erythropoiesis defects in vivo. Using primary erythroblast cultures from these mutants, we present genetic evidence that functional GR, EpoR, and Stat5 are essential for erythroblast renewal in vitro. Cells from GR^dim/dim, EpoR_H, and Stat5ab^–/– mice showed enhanced differentiation instead of renewal, causing accumulation of mature cells and gradual proliferation arrest. Stat5ab was additionally required for Epo-induced terminal differentiation: differentiating Stat5ab^–/– erythroblasts underwent apoptosis instead of erythrocyte maturation, due to absent induction of the antiapoptotic protein Bcl-X_L. This defect could be fully rescued by exogenous Bcl-X_L. These data suggest that signaling molecules driving leukemic proliferation may also be essential for prolonged self-renewal of normal erythroid progenitors.