Histone deacetylase is dysregulated in mesenchymal stromal cells in Philadelphia-negative myeloproliferative neoplasms and functions as potential drug targets

Abstract

Background: Previous studies imply that bone marrow-derived mesenchymal stromal cells (BM-MSCs) supports the progression of Philadelphia-negative myeloproliferative neoplasms (MPN). Histone deacetylases (HDACs) are believed to be promising anti-cancer targets, but its expression characteristics and biological functions in BM-MSCs of MPN patients are unclear. Methods: BM-MSCs were isolated from healthy donors and patients with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Transforming growth factor β1 (TGF-β1) was used to stimulate BM-MSCs, and the expression levels of α-smooth muscle actin (α-SMA), fibroblast activation protein-α (FAP), HDAC1, HDAC2, HDAC3, HDAC8 were detected by qPCR and Western blot. Chidamide was selected as a representative HDAC inhibitor to treat BM-MSCs, and the activation of mTOR pathway was evaluated by Western blot, and the viability of BM-MSCs was examined by flow cytometry. Results: α-SMA and FAP were highly expressed in BM-MSCs of the patients with MPN. HDAC1, HDAC2, and HDAC8 were up-regulated in BM-MSCs of the patients with PMF. TGF-β1 induced up-regulation of α-SMA and FAP, and activation of mTOR signaling in BM-MSCs, while this effect could be reversed by chidamide. Chidamide could also induce the apoptosis of BM-MSCs. Conclusions: Dysregulation of HDACs was involved in pathogenesis of Philadelphia-negative MPN, and HDAC inhibitor such as chidamide may be potential candidate to treat this kind of diseases.