Molecular mechanism of refractoriness of myeloma mediated by adhesion molecules

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Multiple myeloma is one of incurable hematological malignancies. We revealed that functional inhibition of integrin and histone deacetylase (HDAC) blocks proliferation and induces apoptosis in myeloma cells. We discovered that MLL-HOXA9 and PPP3CA, alfa subunit of calcineurin, are inhibited by HDAC inhibitors. We revealed that MLL and PPP3CA are protected from protein degradation by HSP90. HDAC inhibitors induce degradation of MLL and PPP3CA through inhibition of chaperone function of HSP90. It was shown that PPP3CA plays important roles in maintenance of viability of myeloma cells in vitro and in vivo. In clinical samples, PPP3CA expression was high in advanced disease. Osteoclasts formation is essential for osteolytic disease of multiple myeloma. PPP3CA was necessary for formation of osteoclasts and HDAC inhibitors were shown to inhibit osteoclasts formation.