Cdc37 suppression induces plasma cell immaturation and bortezomib resistance in multiple myeloma via Xbp1s
Cdc37 suppression induces plasma cell immaturation and bortezomib resistance in multiple myeloma via Xbp1s
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Cdc37 抑制通过 Xbp1s 诱导多发性骨髓瘤中浆细胞不成熟和硼替佐米耐药
DOI：
10.1038/s41389-020-0216-1
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发表时间：
2020
期刊：
影响因子：
6.2
通讯作者：
Zhou Wen
中科院分区：
文献类型：
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作者：
Zang Meirong;Guo Jiaojiao;Liu Lanting;Jin Fengyan;Feng Xiangling;An Gang;Qin Xiaoqi;Wu Yangbowen;Lei Qian;Meng Bin;Zhu Yinghong;Guan Yongjun;Deng Shuhui;Hao Mu;Xu Yan;Zou Dehui;Wu Minghua;Qiu Lugui;Zhou Wen
多发性骨髓瘤(MM)是第二大最常见的血液系统恶性肿瘤。尽管硼替佐米(BTZ)的使用显著改善了MM的治疗，但对BTZ的固有和获得性耐药仍然是一个主要的临床问题。在这项研究中，我们发现Hsp90的关键辅伴蛋白CDC37在复发的MM患者中表达下调，特别是在BTZ治疗后，这表明CDC37与BTZ耐药之间存在联系。抑制CDC37或抑制CDC37/Hsp90结合可诱导MM浆细胞去分化、MM细胞停滞和BTZ耐药。此外，我们发现CDC37的表达与MM浆细胞分化的关键转录因子Xbp1s呈正相关。CDC37的耗竭/抑制下调了Xbp1s的表达，而Xbp1s在MM细胞系中的过表达部分挽救了胞浆未成熟和BTZ耐药性。提示Xbp1s可能是CDC37下游的关键效应子。用小鼠模型进行的实验也表明，抑制CDC37促进浆细胞不成熟，赋予BTZ耐药性，并增加体内MM的进展。总之，我们确定了调节MM细胞浆细胞不成熟和BTZ耐药性的关键因素和新的信号机制。我们的发现可能构成了一种新的策略，可以克服多发性骨髓瘤治疗中的BTZ耐药性。
Multiple myeloma (MM) is the second most prevalent hematologic malignancy. Although the use of bortezomib (BTZ) significantly improves MM therapy, intrinsic and acquired drug resistance to BTZ remains a major clinical problem. In this study, we find that Cdc37, a key co-chaperone of Hsp90, is downregulated in relapsed MM patients, especially after BTZ treatment, suggesting a link between Cdc37 and BTZ resistance. Suppression of Cdc37 or inhibition of Cdc37/Hsp90 association induces plasma cell dedifferentiation, quiescence of MM cells, and BTZ resistance in MM. Furthermore, we discover that Cdc37 expression correlates positively with Xbp1s, a critical transcription factor for plasma cell differentiation in MM samples. Depletion/inhibition of Cdc37 downregulates Xbp1s, while overexpression of Xbp1s in MM cell lines partially rescues plasma immaturation and BTZ resistance. It is suggested that Xbp1s may act as a key downstream effector of Cdc37. Experiments with a mouse model also demonstrate that Cdc37 inhibition promotes plasma cell immaturation, confers BTZ resistance, and increases MM progression in vivo. Together, we identify a critical factor and a new signaling mechanism that regulate plasma cell immaturation and BTZ resistance in MM cells. Our findings may constitute a novel strategy that overcomes BTZ resistance in MM therapy.