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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-02-0485. This Article Full Text (PDF) All Versions of this Article: 2002-02-0485v1 100/8/2932    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Giraudier, S. Articles by Vainchenker, W. Search for Related Content PubMed PubMed Citation Articles by Giraudier, S. Articles by Vainchenker, W. Social Bookmarking                   What's this? Submitted February 15, 2002 Accepted April 25, 2002 Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors Stephane Giraudier*, Hedia Chagraoui, Emiko Komura, Stephane Barnache, Benoit Blanchet, Jean-Pierre LeCouedic, David F Smith, Frederic Larbret, Anne-Laure Taksin, Francoise Moreau-Gachelin, Nicole Casadevall, Michel Tulliez, Anne Hulin, Najet Debili, and William Vainchenker Institut Gustave Roussy, INSERM Unite 362, Villejuif, France; Laboratoire d Hematologie, Hopital Henri Mondor, Creteil, France Institut Gustave Roussy, INSERM Unite 362, Villejuif, France Institut Curie, INSERM Unite 248, Paris, France Laboratoire de Toxicologie, Hopital Henri Mondor, Creteil, France Mayo Clinic Scottsdale, Scottsdale, AZ, USA Institut Gustave Roussy, INSERM Unite 362, Villejuif, France; Laboratoire d Hematologie, Hopital Hotel-Dieu, Paris, France Laboratoire d Hematologie, Hopital Henri Mondor, Creteil, France * Corresponding author; email: stephane.giraudier{at}hmn.ap-hop-paris.fr. Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by megakaryocyte hyperplasia and bone marrow fibrosis. Biologically, an autonomous megakaryocyte growth and differentiation is noticed which contributes to the megakaryocyte accumulation. To better understand the molecular mechanisms involved in this spontaneous growth, we searched for genes differentially expressed between normal megakaryocytes requiring cytokines to grow and IMF spontaneously proliferating megakaryocytes. Using a differential display technique, we found that the immunophilin FKBP51 was 2 to 8 times overexpressed in megakaryocytes derived from patients CD34+ cells in comparison to normal megakaryocytes. Overexpression was moderate and confirmed in 8 out of 10 patients, both at the mRNA and protein levels. Overexpression of FKBP51 in a UT-7/Mpl cell line and in normal CD34+ cells induced a resistance to apoptosis mediated by cytokine deprivation with no effect on proliferation. FKBP51 interacts with both calcineurin and HSP90. However, a mutant FKBP51 deleted in the HSP90 binding site kept the anti-apoptotic effect suggesting that the calcineurin pathway was responsible of the FKBP51 effect. Overexpression of FKBP51 in UT-7/Mpl cells induced a marked inhibition of calcineurin activity. Pharmacologic inhibition of calcineurin by cyclosporin A mimicked the effect of FKBP51. The data support the conclusion that FKBP51 inhibits apoptosis through a calcineurin dependant pathway. In conclusion, FKBP51 is overexpressed in IMF megakaryocytes and this overexpression could be in part responsible of the megakaryocytic accumulation observed in this disorder by regulating their apoptotic program. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Li, B. Fridley, K. Kalari, G. Jenkins, A. Batzler, S. Safgren, M. Hildebrandt, M. Ames, D. Schaid, and L. 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