A critical role for the NFkB pathway in multiple myeloma

NFkB transcription factors play a key role in the survival and proliferation of many kinds of B-cell tumors, including multiple myeloma (MM). It was shown that NFkB activation in MM tumors results mainly from extrinsic signaling by APRIL and BAFF ligands that stimulate receptors on normal plasma cells as well as on pre-malignant monoclonal gammopathy of undetermined significance (MGUS) and MM tumors. However, the mutations that occur during MM progression and that constitutively activate NFkB would be expected to decrease dependence of tumor cells on the bone marrow microenvironment. These mutations can activate the classical or alternative NFkB pathways selectively, but usually both pathways are activated in MM. Significantly, activation of either NFkB pathway leads to a similar response of MM cell lines. This frequent activation of the alternative pathway distinguishes MM from other B-cell tumors, which more frequently have mutations that are predicted to activate only the classical NFkB pathway. Given the strong dependence of MGUS and MM tumors on NFkB pathway activation, inhibition by a combination of targeting extrinsic signaling plus both NFkB pathways appears to be an attractive therapeutic approach in MM tumors.