Osteoclasts Control Re-activation of Dormant Myeloma Cells by Remodeling the Endosteal Niche

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 re-populate the tumor. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and re-activation. 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 which is switched on by engagement with bone lining cells or osteoblasts, and switched off by osteoclasts remodeling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy targeting 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.

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Lawson MA, McDonald MM, Kovacic N, Hua Khoo W, Terry RL, Down J, Kaplan W, Paton-Hough J, Fellows C, Pettitt JA, Neil Dear T, Van Valckenborgh E, Baldock PA, Rogers MJ, Eaton CL, Vanderkerken K, Pettit AR, Quinn JM, Zannettino AC, Phan TG, Croucher PI