Bone Abstracts

Multiple myeloma (MM) bone disease is characterized by lytic bone lesions that contribute to patient morbidity and mortality after patients are in complete remission. The mechanisms mediating this long-term osteoblast (OB) suppression are poorly understood. We hypothesized that MM cells induce epigenetic changes at the Runx2 promoter in preOB bone marrow stromal cells (BMSC). We demonstrated that Gfi1, a transcriptional repressor of Runx2 that is induced in BMSC by MM, directly binds to the Runx2 promoter, recruiting chromatin corepressors and inducing epigenetic repression of Runx2 in preOB, thereby preventing OB differentiation.

We reported that p62 (sequestosome-1) in BMSC is critical for the formation of MM-induced signaling complexes that mediate OB suppression, and found that an inhibitor of the p62 ZZ domain, XRK3F2, blunted MM cell-induced Runx2 suppression and Gfi1 induction in murine preOB. In vivo, XRK3F2 induced new bone formation and remodeling in the presence of high tumor burden without altering bones without tumor.

We tested if XRK3F2 prevents the Gfi1-mediated epigenetic suppression of Runx2 observed following MM exposure. ChIP analysis of murine preOB exposed to MM ± XRK3F2 demonstrated that XRK3F2 prevented MM-induced Runx2 promoter Gfi1 occupancy, recruitment of the chromatin corepressor HDAC1, and histone de-acetylation. Coculture experiments using human MM cells and murine preOB showed that XRK3F2 both prevents and reverses Gfi1 upregulation. Importantly, long-term culture of primary MM patient BMSC with XRK3F2 increased acetylation at the Runx2 promoter, allowing rescued osteogenic differentiation and mineral deposition.

We conclude that XRK3F2 blocks MM-induced signaling, reducing recruitment of Gfi1 and its corepressor HDAC1 to the Runx2 promoter, and preventing MM-induced epigenetic suppression of Runx2. These results suggest that targeting p62-ZZ as a therapeutic strategy in MM may reverse Gfi1 upregulation, rescuing MM-induced epigenetic suppression of Runx2 in BMSC and healing MM bone lesions.