Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy in the bone marrow characterized by chromosome instability (CIN), which contributes to the acquisition of heterogeneity, along with MM progression, drug resistance, and relapse. In this study, we elucidated that the expression of BUB1B increased strikingly in MM patients and was closely correlated with poor outcomes. Overexpression of BUB1B facilitated cellular proliferation and induced drug resistance in vitro and in vivo, while genetic targeting BUB1B abrogated this effect. Mechanistic studies unveiled that enforced expression of BUB1B evoked CIN resulting in MM poor outcomes mainly through phosphorylating CEP170. Interestingly, we discovered the existence of circBUB1B_544aa containing the kinase catalytic center of BUB1B, which was translated by a circular RNA of BUB1B. The circBUB1B_544aa elevated in MM peripheral blood samples was closely associated with MM poor outcomes and played a synergistic effect with BUB1B on evoking CIN. In addition, MM cells could secrete circBUB1B_544aa and interfere the MM microenvironmental cells in the same manner as BUB1B full-length protein. Intriguingly, BUB1B siRNA, targeting the kinase catalytic center of both BUB1B and circBUB1B_544aa, significantly inhibited MM malignancy in vitro and in vivo. Collectively, BUB1B and circBUB1B_544aa are promising prognostic and therapeutic targets of MM.
Highlights
Multiple myeloma (MM) is a molecularly and cytogenetically heterogeneous hematological malignancy that originates in the bone marrow (BM)
Heightened expression of BUB1B is correlated with poor survival in MM To explore the role of BUB1B in MM, the gene expression profiling (GEP) dataset of normal plasma (NP), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), multiple myeloma (MM), and relapse multiple myeloma (RMM) were analyzed initially
The expression of BUB1B was associated with inferior outcome in HOVON65 (p < 0.0001) (Fig. 1b) and TT2 (p < 0.0001) (Fig. 1c) patient cohorts, suggesting that BUB1B is a potential biomarker of MM poor prognosis
Summary
Multiple myeloma (MM) is a molecularly and cytogenetically heterogeneous hematological malignancy that originates in the bone marrow (BM). Despite the targeted drugs, such as immune modulators and proteasome inhibitors, have greatly improved the outcome of MM patients over the decades, MM remains lifethreatening and incurable.[1,2] It is well known that genetic and epigenetic aberrations, clonal heterogeneity, and clonal evolution play indispensable roles in MM progression, drug resistance and relapse. The molecular basis of MM pathogenesis still has not been fully understood. Our studies pointed out that chromosomal instability (CIN) accelerated the development of MM malignancy and drug resistance, leading to the treatment failure and relapse, which limited the effectiveness of most current therapies.[3,4] identification of novel molecules and signaling pathways involved in the relationship between CIN and MM is fundamentally essential
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