骨髓瘤干细胞（MMSC）是导致多发性骨髓瘤（MM）患者复发和死亡的主要根源。我们前期研究发现：MMSC高表达维甲酸受体α2（RARα2），它能够上调NANOG并可以与其结合。RARα2依赖Wnt/Hh/TCF3通路调控MMSC，通过阻断Wnt 和 Hh通路，在体内外都能够导致MMSC死亡。与MM细胞相比较，MMSC表面CD38表达明显下降，全反式维甲酸（ATRA）能上调MMSC 的CD38表达。据此我们假设：通过ATRA诱导MMSC的CD38表达，再联合人源化抗CD38抗体（DARA）、Wnt抑制剂（塞来昔布）和Hh抑制剂（伊曲康唑）诱导MMSC凋亡，会有效杀死MMSC。本项目将研究NANOG 在RARα2调控MMSC“干性”中的作用及信号网络；探索ATRA和DARA联合对MMSC的杀伤作用及机制；开展联合ATRA、塞来昔布和伊曲康唑治疗复发/难治MM的临床试验，为靶向MMSC提供新思路。

Multiple myeloma (MM) patients ultimately relapse and die of their disease due to the persistence of myeloma stem cells (MMSC). Our preliminary data indicate that MMSC have high expression of retinoic receptor α2 (RARα2). RARα2 mediates myeloma stemness depending on Wnt, Hh, TCF3 pathways. RARα2 directly upregulates and binds to NANOG. Blocking Wnt and Hh pathways results in MMSC death in vivo and in vitro. All-trans-retinoic acid (ATRA) upregulates CD38 expression, which is significantly lower in MMSC, compared to the MM cells. Based on our findings, we thus hypothesize that CD38 expression can be induced by ATRA, and the combination of ATRA, humanized anti-CD38 antibody (daratumumab, DARA), Wnt inhibitor (celecoxib) and Hh inhibitor (itraconazole) may induce the apoptosis of MMSC and eradicate MMSC effectively. In this project, we will investigate the functional role and signal network of NANOG in RARα2 mediated effects on MMSC features, explore the killing effect and mechanism on MMSC by combination of ATRA and DARA, perform a clinical study by combining ATRA, celecoxib and itraconazole for relapsed/refractory MM. Our studies should provide a novel thought in targeting MMSC.