DataSheet_1_Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma.docx

Inositol polyphosphate-4-phosphatase type II (INPP4B) has been identified as a tumor suppressor, while little is known about its expression and function in multiple myeloma (MM). In this study, we evaluated the expression of INPP4B in 28 cases of newly diagnosed MM patients and 42 cases of extramedullary plasmacytoma (EMP) patients compared with normal plasma cells and found that low INPP4B expression was correlated with poor outcomes in MM patients. Moreover, expression of INPP4B in seven MM cell lines was all lower than that in normal plasma cells. In addition, loss of function of INPP4B promoted cell proliferation in MM cells; however, gain of function suppressed MM cells proliferation and arrested the cell cycle at G0/G1 phage. Meanwhile, knockdown of INPP4B enhanced resistance, but overexpression promoted sensitivity to bortezomib treatment in MM cells. Mechanistically, we found that INPP4B exerted its role via inhibiting the phosphorylation of Akt at lysine 473 but not threonine 308, which attenuated the activation of the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Therefore, we identified an inhibitory effect of INPP4B in MM, and our findings suggested that loss of INPP4B expression is a risk factor of aggressive MM.II型肌醇多磷酸-4-磷酸酶（Inositol polyphosphate-4-phosphatase type II，INPP4B）已被证实为肿瘤抑制因子，但目前对于其在多发性骨髓瘤（multiple myeloma，MM）中的表达与功能尚不清楚。本研究以正常浆细胞为对照，检测了28例初诊MM患者及42例髓外浆细胞瘤（extramedullary plasmacytoma，EMP）患者样本中INPP4B的表达水平，结果发现INPP4B低表达与MM患者的不良预后显著相关。此外，7株MM细胞系中INPP4B的表达水平均低于正常浆细胞。进一步实验显示，INPP4B功能缺失可促进MM细胞增殖；而INPP4B功能过表达则抑制MM细胞增殖，并将细胞周期阻滞于G0/G1期。同时，敲低INPP4B可增强MM细胞对硼替佐米的耐药性，而过表达INPP4B则可提高MM细胞对硼替佐米的敏感性。机制研究表明，INPP4B通过抑制Akt在赖氨酸473位点的磷酸化（而非苏氨酸308位点），减弱PI3K/Akt/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路的激活。综上，本研究证实了INPP4B在MM中的抑癌作用，且研究结果提示INPP4B表达缺失是侵袭性MM的危险因素。