![]() ![]() Our previous study showed that DKK1 expression was very high in nearly 80% of newly diagnosed patients but was essentially undetectable in plasma cells from control subjects and those with Waldenström macroglobulinemia and monoclonal gammopathy of undetermined significance (MGUS), 2 plasma cell dyscrasias involving the bone marrow not associated with lytic bone disease. We conclude that specific strategies to modulate persistent activation of the JNK pathway may be beneficial in preventing disease progression and treating myeloma-associated bone disease by inhibiting DKK1 expression.Īlthough the biologic function of DKK1 in MM pathophysiology has recently begun to be elucidated, 9, 12 it is currently not known how DKK1 expression is activated and regulated in MM plasma cells during different stages of disease. Despite its role as a tumor suppressor and mediator of apoptosis in other cell types including osteoblasts, our data suggest that DKK1, a stress-responsive gene in MM, does not mediate apoptotic signaling, is not activated by TP53, and its forced overexpression could not inhibit cell growth or sensitize MM cells to apoptosis following treatment with thalidomide or lenalidomide. Herein, we could trace DKK1 expression changes in MM cells to perturbations in the JNK signaling cascade, which is differentially modulated through oxidative stress and interactions between MM cells with osteoclasts in vitro. The mechanisms responsible for activation and regulation of DKK1 expression in MM are not known. We previously reported that secretion of DKK1 by MM cells likely contributes to osteolytic lesions in this disease by inhibiting Wnt signaling, which is essential for osteoblast differentiation and survival. ![]() Multiple myeloma (MM) plasma cells, but not those from healthy donors and patients with monoclonal gammopathy of undetermined significance or other plasma cell dyscrasias involving the bone marrow, express the Wnt-signaling antagonist DKK1. ![]()
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