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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-02-0485.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2932-2940
NEOPLASIA
Overexpression of FKBP51 in idiopathic myelofibrosis regulates
the growth factor independence of megakaryocyte
progenitors
Stéphane Giraudier,
Hédia Chagraoui,
Emiko Komura,
Stéphane Barnache,
Benoit Blanchet,
Jean Pierre LeCouedic,
David F. Smith,
Frédéric Larbret,
Anne-Laure Taksin,
Françoise Moreau-Gachelin,
Nicole Casadevall,
Michel Tulliez,
Anne Hulin,
Najet Debili, and
William Vainchenker
From the INSERM U362, Pavillon de recherche 1, Institut
Gustave Roussy, Villejuif Cedex, France; Laboratoire
d'Hématologie and Laboratoire de Toxicologie, Hôpital
Henri Mondor, Créteil, France; INSERM U248 Institut Curie and
Laboratoire d'Hématologie, Hôpital de l'Hotel-Dieu,
Paris, France; and the Mayo Clinic Scottsdale, Scottsdale, Arizona.
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 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 heat shock
protein (HSP)70/HSP90. However, a mutant FKBP51 deleted in the
HSP70/HSP90 binding site kept the antiapoptotic effect, suggesting that
the calcineurin pathway was responsible for 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-dependent pathway. In conclusion, FKBP51 is overexpressed
in IMF megakaryocytes and this overexpression could be, in part,
responsible for the megakaryocytic accumulation observed in this
disorder by regulating their apoptotic program.
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