Blood Journal
Leading the way in experimental and clinical research in hematology

Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation

  1. Katrin Friedbichler1,
  2. Marc A. Kerenyi2,
  3. Boris Kovacic3,
  4. Geqiang Li4,
  5. Andrea Hoelbl5,
  6. Saliha Yahiaoui6,
  7. Veronika Sexl5,
  8. Ernst W. Müllner7,
  9. Sabine Fajmann5,
  10. Sabine Cerny-Reiterer8,
  11. Peter Valent8,9,
  12. Hartmut Beug3,
  13. Fabrice Gouilleux10,
  14. Kevin D. Bunting4, and
  15. Richard Moriggl1
  1. 1Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria;
  2. 2Department of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA;
  3. 3Research Institute of Molecular Pathology (IMP), Vienna, Austria;
  4. 4Division of Hematology/Oncology, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH;
  5. 5Institute of Pharmacology, Medical University of Vienna, Vienna, Austria;
  6. 6Inserm U925, Faculté de Médecine, Université de Picardie J. Verne, Amiens, France;
  7. 7Max F. Perutz Laboratories, Department of Medical Biochemistry, and
  8. 8Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria;
  9. 9Ludwig Boltzmann Cluster Oncology, Vienna, Austria; and
  10. 10Centre National de la Recherche Scientifique (CNRS) UMR 6239, Université F. Rabelais, UFR Médecine, Tours, France


Stat5 transcription factors are essential gene regulators promoting proliferation, survival, and differentiation of all hematopoietic cell types. Mutations or fusions of oncogenic tyrosine kinases often result in constitutive Stat5 activation. We have modeled persistent Stat5 activity by using an oncogenic Stat5a variant (cS5). To analyze the hitherto unrecognized role of Stat5 serine phosphorylation in this context, we have generated cS5 constructs with mutated C-terminal serines 725 and 779, either alone or in combination. Genetic complementation assays in primary Stat5null/null mast cells and Stat5ΔN T cells demonstrated reconstitution of proliferation with these mutants. Similarly, an in vivo reconstitution experiment of transduced Stat5null/null fetal liver cells transplanted into irradiated wild-type recipients revealed that these mutants exhibit biologic activity in lineage differentiation. By contrast, the leukemogenic potential of cS5 in bone marrow transplants decreased dramatically in cS5 single-serine mutants or was completely absent upon loss of both serine phosphorylation sites. Our data suggest that Stat5a serine phosphorylation is a prerequisite for cS5-mediated leukemogenesis. Hence, interference with Stat5a serine phosphorylation might provide a new therapeutic option for leukemia and myeloid dysplasias without affecting major functions of Stat5 in normal hematopoiesis.

  • Submitted December 14, 2009.
  • Accepted May 15, 2010.
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