Citations

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.

Background— The outcome of mitral valve prolapse (MVP) is controversial, with marked discrepancies in reported complication rates. Methods and Results— We conducted a community study of all Olmsted County, Minn, residents first diagnosed with asymptomatic MVP between 1989 and 1998 (N=833). Diagnosis, motivated by auscultatory findings (n=557) or incidental (n=276), was always confirmed by echocardiography with the use of current criteria. End points analyzed during 4581 person-years of follow-up were mortality (n=96, 19±2% at 10 years), cardiovascular morbidity (n=171), and MVP-related events (n=109, 20±2% at 10 years). The most frequent primary risk factors for cardiovascular mortality were mitral regurgitation from moderate to severe ( P =0.002, n=131) and, less frequently, ejection fraction <50% ( P =0.003, n=31). Secondary risk factors independently predictive of cardiovascular morbidity were slight mitral regurgitation, left atrium ≥40 mm, flail leaflet, atrial fibrillation, and age ≥50 years (all P <0.01). Patients with only 0 or 1 secondary risk factor (n=430) had excellent outcome, with 10-year mortality of 5±2% ( P =0.17 versus expected), cardiovascular morbidity of 0.5%/y, and MVP-related events of 0.2%/y. Patients with ≥2 secondary risk factors (n=250) had mortality similar to expected ( P =0.20) but high cardiovascular morbidity (6.2%/y, P <0.01) and notable MVP-related events (1.7%/y, P <0.01). Patients with primary risk factors (n=153) showed excess 10-year mortality (45±9%, P =0.01 versus expected), high morbidity (18.5%/y, P <0.01), and high MVP-related events (15%/y, P <0.01). Conclusions— Natural history of asymptomatic MVP in the community is widely heterogeneous and may be severe. Clinical and echocardiographic characteristics allow separation of the majority of patients with excellent prognosis from subsets of patients displaying, during follow-up, high morbidity or even excess mortality as direct a consequence of MVP.