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.

多发性骨髓瘤（MM）是第二大最常见的血液系统恶性肿瘤。尽管使用硼替佐米（BTZ）可以显着改善MM治疗，但对BTZ的固有耐药性和获得性耐药仍是主要的临床问题。在这项研究中，我们发现Hsp90的关键辅助伴侣Cdc37在复发的MM患者中被下调，尤其是在BTZ治疗后，提示Cdc37与BTZ耐药性之间存在联系。Cdc37的抑制或Cdc37 / Hsp90关联的抑制诱导浆细胞去分化，MM细胞静止和MM中的BTZ抵抗力。此外，我们发现Cdc37表达与Xbp1s正相关，Xbp1s是MM样品中浆细胞分化的关键转录因子。消耗/抑制Cdc37下调Xbp1，而Xbp1s在MM细胞系中的过表达部分地挽救了血浆不成熟和BTZ抵抗力。建议Xbp1s可能是Cdc37的关键下游效应子。小鼠模型的实验还表明，Cdc37抑制作用可促进浆细胞不成熟，赋予BTZ抗性并增加体内MM的进展。在一起，我们确定了一个关键因素和一个新的信号传导机制，可调节MM细胞中的浆细胞不成熟和BTZ抵抗力。我们的发现可能构成克服MM治疗中BTZ抵抗的新策略。我们确定了一个关键因素和新的信号传导机制，可调节MM细胞中的浆细胞不成熟和BTZ抵抗力。我们的发现可能构成克服MM治疗中BTZ抵抗的新策略。我们确定了一个关键因素和新的信号传导机制，可调节MM细胞中的浆细胞不成熟和BTZ抵抗力。我们的发现可能构成克服MM治疗中BTZ抵抗的新策略。