Molecular mechanism of refractoriness of myeloma mediated by adhesion molecules

多发性骨髓瘤是一种难以治愈的血液系统恶性肿瘤。我们发现，功能性抑制整合素和组蛋白脱乙酰酶（HDAC）阻断骨髓瘤细胞的增殖和诱导凋亡。我们发现MLL-HOXA 9和PPP 3CA，钙调磷酸酶的α亚基，被HDAC抑制剂抑制。我们发现，MLL和PPP 3CA的保护，从蛋白质降解的HSP 90。HDAC抑制剂通过抑制HSP 90的伴侣功能诱导MLL和PPP 3CA的降解。结果表明，PPP 3CA在体外和体内维持骨髓瘤细胞的活力中起重要作用。在临床样本中，PPP 3CA表达在晚期疾病中较高。破骨细胞的形成是多发性骨髓瘤溶骨性疾病的基础。PPP 3CA是破骨细胞形成所必需的，HDAC抑制剂显示出抑制破骨细胞形成。

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.