Multiple myeloma (MM) is an incurable hematological malignancy. The bone marrow immune microenvironment plays a crucial role in MM progression. Our previous studies have shown that natural killer (NK) cell function is depleted in the bone marrow microenvironment of patients with MM. Therefore, it is urgent to explore the mechanisms underlying NK cell depletion and identify potential therapeutic targets. In this study, we focused on the mechanisms and potential therapeutic targets of MM osteoblasts that promote bone marrow NK cell depletion. The receptor activator of NF-kappa B (RANK) expression in bone marrow NK cells of patients with MM was significantly higher than that in normal controls. Serum receptor activator of NF-kappa B ligand (RANKL) levels in patients with MM also significantly higher than those in normal controls. MM cells can induce RANK expression in NK cells. Moreover, it is osteoblasts—not bone marrow mesenchymal stem cells—that secrete more RANKL. Blocking RANKL with denosumab resulted in increased CD107a expression, decreased KIR3DL1 expression, and increased release of perforin and granzyme B in NK cells. In addition, apoptosis was significantly increased in MM cells. Bone marrow osteoblasts in patients with MM may inhibit NK cell function via RANK/RANKL. Furthermore, denosumab combined with lenalidomide or pomalidomide can improve bone marrow NK cell function in these patients.
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