Role for the nuclear factor κB pathway in transforming growth factor-β1 production in idiopathic myelofibrosis: Possible relationship with FK506 binding protein 51 overexpression

The release of transforming growth factor-β1 (TGF-β1) in the bone marrow microenvironment is one of the main mechanisms leading to myelofibrosis in marine models and probably in the human idiopathic myelofibrosis (IMF). The regulation of TGF-β1 synthesis is poorly known but seems regulated by nuclear factor κB (NF-κB). 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-κB activation after cytokine deprivation. This activation correlates with a low level of IκBα. A spontaneous activation of NF-κB was also detected in proliferating megakaryocytes and in circulating CD34⁺ patient cells. In normal cells, NF-κB activation was only detected after cytokine treatment. The expression of an NF-κB superrepressor in FKBP51 over-expressing cells and in derived megakaryocytes from CD34⁺ of IMF patients revealed that NF-κB activation was not involved in the resistance to apoptosis after cytokine deprivation of these cells but in TGF-β1 secretion. These results highlight the importance of NF-κB'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.