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

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.

Endoplasmic reticulum stress and proteasome inhibitors in multiple myeloma – a room for improvement

“…Intriguingly, the study also showed that the expression of IRE1 in posttreatment samples from refractory patients (disease progressed during treatment) is significantly lower than in paired pre-treatment specimens. The authors, similarly to Zang et al [45], explain this counter-intuitive finding by clonal selection. Thus, with this complexity in mind, efficacy of IRE1 inhibition in PI-resistant setting remains to be determined.…”

“…Interestingly, the latter conclusion is not true for patients treated with thalidomide, underpinning that this mechanism is PI-specific [44]. In a recent study Zang et al [45] linked the XBP1s-low phenotype with expression of Cdc37 (cell division cycle 37), a co-chaperone of Hsp90 (heat shock protein 90), another chaperone stabilizing many oncogenes [46], and confirmed its impact on bortezomib resistance. They also provided interesting explanation of discrepancies between high Cdc37 expression in NDMM samples in contrast to low expression in bortezomib-resistant samples from RR MM patients, attributing it to the clonal selection [47] common phenomenon that includes also evolution of cytogenetic lesions [48].…”

A drug repurposing strategy for overcoming human multiple myeloma resistance to standard-of-care treatment

“…For example treatment resistance in some MM patients can reflect expansion of Xbp1s low B tumor cells and pre-plasmablasts which are intrinsically resistant to bortezomib due to lower immunoglobulin production and decreased proteasome load [ 19 ], thus supporting the load-versus-capacity theory [ 20 ]. Others confirmed a correlation of the low-level XBP1s and immunoglobulin production with poor responses to bortezomib therapy [ 21 ] or decreased sensitivity in vitro [ 22 ]. In terms of the MM secretory status, patients with measurable disease responded to bortezomib better than oligo- or non-secretory MM patients [ 23 ] consistent with Ig production/secretion sensitizing MM to bortezomib [ 24 ].…”

Multiple myeloma hinders erythropoiesis and causes anaemia owing to high levels of CCL3 in the bone marrow microenvironment

“…Immunofluorescence was performed as previously described 48 . HSPCs were spun down on glass slides and then fixed in − 20 °C acetone/methanol (1:1 volume) for 10 min.…”

“…Six weeks after tumour cell injection, the mice were euthanized humanely and processed to evaluate erythropoiesis in vivo. Bone marrow was collected and detected by flow cytometry as previously reported48 .…”