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Role for the Nuclear Factor B Pathway in Transforming Growth Factor-ß1 Production in Idiopathic Myelofibrosis: Possible Relationship with FK506 Binding Protein 51 Overexpression

¹ Institut National de la Sante et de la Recherche Medicale U362, Institut Gustave Roussy, Villejuif, France; ² Laboratoire d'Hématologie, Hôpital Henri Mondor, Créteil, France; and ³ EMI0210, Tour Pasteur, Hôpital Necker-Enfants Malades, Paris, France

Requests for reprints: Stéphane Giraudier, Institut National de la Sante et de la Recherche Medicale U362, Pavillon de recherche 1, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805, Villejuif Cedex, France. Phone: 33-1-4211-5233; Fax: 33-1-4211-5240; E-mail: stephane.giraudier{at}hmn.ap-hop-paris.fr.

The release of transforming growth factor-ß1 (TGF-ß1) in the bone marrow microenvironment is one of the main mechanisms leading to myelofibrosis in murine models and probably in the human idiopathic myelofibrosis (IMF). The regulation of TGF-ß1 synthesis is poorly known but seems regulated by nuclear factor B (NF-B). We previously described the overexpression of an immunophilin, FK506 binding protein 51 (FKBP51), in IMF megakaryocytes. Gel shift and gene assays show that FKBP51's overexpression in a factor-dependent hematopoietic cell line, induces a sustained NF-B activation after cytokine deprivation. This activation correlates with a low level of IB. A spontaneous activation of NF-B was also detected in proliferating megakaryocytes and in circulating CD34⁺ patient cells. In normal cells, NF-B activation was only detected after cytokine treatment. The expression of an NF-B superrepressor in FKBP51 overexpressing cells and in derived megakaryocytes from CD34⁺ of IMF patients revealed that NF-B activation was not involved in the resistance to apoptosis after cytokine deprivation of these cells but in TGF-ß1 secretion. These results highlight the importance of NF-B's activation in the fibrosis development of this disease. They also suggest that FKBP51's overexpression in IMF cells could play an important role in the pathogenesis of this myeloproliferative disorder.

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