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.

多发性骨髓瘤 (MM) 是骨髓中一种无法治愈的浆细胞恶性肿瘤，其特征是染色体不稳定 (CIN)，这会导致异质性的获得，以及 MM 的进展、耐药性和复发。在这项研究中，我们阐明了 BUB1B 的表达在 MM 患者中显着增加，并且与不良预后密切相关。 BUB1B 的过度表达促进细胞增殖并在体外和体内诱导耐药性，而基因靶向 BUB1B 消除了这种效应。机制研究揭示，BUB1B 的强制表达主要通过磷酸化 CEP170 诱发 CIN，导致 MM 不良预后。有趣的是，我们发现了包含BUB1B激酶催化中心的circBUB1B_544aa的存在，该中心由BUB1B的环状RNA翻译。 MM外周血样本中circBUB1B_544aa升高与MM不良预后密切相关，并与BUB1B在诱发CIN方面发挥协同作用。此外，MM细胞可以分泌circBUB1B_544aa并以与BUB1B全长蛋白相同的方式干扰MM微环境细胞。有趣的是，BUB1B siRNA 靶向 BUB1B 和 circBUB1B_544aa 的激酶催化中心，在体外和体内显着抑制 MM 恶性肿瘤。总的来说，BUB1B 和 circBUB1B_544aa 是有希望的 MM 预后和治疗靶点。