Cdc37 suppression induces plasma cell immaturation and bortezomib resistance in multiple myeloma via Xbp1s

Lugui Qiu,Minghua Wu,Jiaojiao Guo,Yongjun Guan,Yinghong Zhu,Dehui Zou,Wen Zhou,Yan Xu,Shuhui Deng,Bin Meng,Xiangling Feng,Meirong Zang,Lanting Liu,Mu Hao,Fengyan Jin,Gang An,Xiaoqi Qin,Yangbowen Wu,Qian Lei

doi:10.1038/s41389-020-0216-1

Abstract

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.

Highlights

Multiple myeloma (MM) is a plasma cell neoplasia characterized by clonal expansion of malignant plasma cells and production of large amounts of monoclonal immunoglobulins (Ig)[1]
Our study suggests that Cdc[37] may serve as a reliable, clinically useful molecule that may be used for predicting drug resistance and developing novel therapeutic strategies in MM treatment
The gene expression analysis revealed that five MM patients (P1–P5) underwent significant downregulation of Cdc[37] at one or more time points after treatments compared with the baseline (Fig. 1a)

Summary

Introduction

Multiple myeloma (MM) is a plasma cell neoplasia characterized by clonal expansion of malignant plasma cells and production of large amounts of monoclonal immunoglobulins (Ig)[1]. Despite the advances in the regimens of MM treatment, MM remains incurable due to intrinsic or acquired drug resistance[2]. We previously identified several highly expressed chromosome instability genes involved in drug resistance in sequential MM samples[4]. We discovered Cdc[37] as a gene that is downregulated with disease progression. Cdc[37] is a key co-chaperone of Hsp[90], acting as an adaptor to load protein kinases to the Hsp[90] complex, to regulate the function of Hsp[90] with temporal specificity and substrate selectivity, and to guide the stabilization and activation of protein kinases[5,6,7]. It has been shown that Cdc[37] is required for chromosome segregation, cytokinesis, and proliferation in many normal cell

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Results

Conclusion