Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms

摘要

Myeloproliferation, myeloaccumulation (decreased apoptosis), inflammation, bone marrow fibrosis and angiogenesis are cardinal features of the Philadelphia-negative chronic myeloproliferative neoplasms: essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Histone deacetylases (HDACs) have a critical role in modulating gene expression and, accordingly, in the control of cell pathobiology and cancer development. HDAC inhibition has been shown to inhibit tumor growth (impaired myeloproliferation), to modulate the balance between pro- and antiapoptotic proteins in favor of apoptosis (enhanced apoptosis) and also to inhibit angiogenesis. Recently, enhanced HDAC enzyme activity has been found in CD34+cells from patients with PMF, enzyme activity levels highly exceeding those recorded in other chronic myeloproliferative neoplasms (CMPNs). The raised levels correlated to the degree of splenomegaly, suggesting that HDAC might be recruited as ET or PV progresses into myelofibrosis or PMF progresses into a more advanced stage. Accordingly, HDAC inhibition is an obvious novel therapeutic approach in these neoplasms. Using global gene expression profiling of whole blood from patients with CMPNs, we have found a pronounced deregulation of HDAC genes, involving significant up-regulation of the HDAC genes 9 and 11, with the highest expression levels being found in patients with ET (HDAC9 and 11), PMF (HDAC9) and CMPNs (both HDAC9 and HDAC11). Furthermore, we have identified that the HDAC6 gene is progressively expressed in patients with ET, PV and PMF, reflecting a steady accumulation of abnormally expressed HDAC6 during disease evolution. Our results lend further support to HDACs as important epigenetic targets in the future treatment of patients with CMPNs. Since the highest expression levels of HDAC genes were recorded in ET, in PMF and in the entire CMPN group, their down-regulation by HDAC inhibitors might be associated with decreased disease activity, including reduction of splenomegaly.