Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state that is switched 'on' by engagement with bone-lining cells or osteoblasts, and switched 'off' by osteoclasts remodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targets dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse.

中文翻译：

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破骨细胞通过重塑骨内膜生境来控制休眠的骨髓瘤细胞的活化。

尽管开发了针对骨髓瘤细胞内源性途径的疗法，但多发性骨髓瘤基本上无法治愈。疾病复发被认为起源于休眠的骨髓瘤细胞，这些细胞位于专门的小生境中，这些小生境抵抗治疗并重新聚集肿瘤。然而，关于生态位及其如何对骨髓瘤细胞休眠和激活进行细胞外源性控制知之甚少。在这项研究中，我们通过活体成像追踪单个骨髓瘤细胞，因为它们定居于骨内膜生境，进入休眠状态，随后被激活以形成菌落。我们证明休眠是一种可逆的状态，通过与骨衬细胞或成骨细胞的结合而被“打开”，而由破骨细胞重塑了骨内膜生境而被“关闭”了。休眠骨髓瘤细胞对靶向分裂细胞的化学疗法具有抗性。骨内膜小生境在控制骨髓瘤细胞休眠中起着关键作用的证明突出了靶向细胞外源性机制克服细胞内在性耐药性和预防疾病复发的潜力。