Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors

Abstract

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.

Pathogenetic insight and prognostic information from standard and molecular cytogenetic studies in the BCR-ABL-negative myeloproliferative neoplasms (MPNs)

“…It has been suggested that this protein may confer an anti-apoptotic effect through inhibition of calcineurin. 32 Finally, a patient with PMF and t(5;12)(q22;q13), associated with a novel TEL-PDGFRb fusion transcript, has been reported that responded to imatinib therapy. This case suggests that tyrosine kinase activations other than JAK2 and MPL mutations may also be responsible for the pathogenesis of rare cases of PMF.…”

Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids

“…They con-tain an N-terminal peptidylprolyl cis-trans isomerase domain and a C-terminal tetratricopeptide repeat domain that participates in protein-protein interactions. In addition to modulating steroid receptor function (Denny et al 2000;Galigniana et al 2001;Hubler et al 2003;Riggs et al 2003), the large molecular weight FKBPs have been shown to play a role in a number of biochemical processes including regulation of transient receptor potential-like calcium channels (Goel et al 2001), apoptosis (Giraudier et al 2002), transduction efficiency of viral vectors (Qing et al 2001), and gene transcription (Mamane et al 2000;Guo et al 2001). Given their diverse functions, it is important to understand how the expression of these proteins is regulated.…”

mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL

“…However, a correlation between mRNA and protein levels has been shown previously for HSP-90, HSP-70, BAG-1, FKBP-51 and FKBP-52 in different cell lines. [27][28][29][30][31] Owing to the limitation of patient material, it was not possible to confirm these data in our population. Another hypothesis relating (co)chaperone molecules to GC resistance might be that not the expression level but rather the functional capacity of the (co)chaperone molecules to form a complex with the GR instead of the expression level of the (co)chaperone molecules is related to GC resistance.…”