Multiple Myeloma: bench to bedside.

Abstract

Disease progression is a major obstacle to achieving cure in patients with multiple myeloma (MM). Recent clinical studies suggest the contribution of infections to MM progression; however, the underlying mechanisms remain unexplained. In our cohort of MM patients, we found that disease progression frequently occurred after bacterial infections. The CD180/MD-1 complex, one of LPS receptors, was specifically expressed on MM cells and its abundance was markedly up-regulated under adherent and hypoxic conditions. Bacterial LPS enhanced the growth of MM cells in positive correlation with the expression levels of CD180 in vitro and in vivo. We identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene. Accordingly, genetic and pharmacological targeting of Ikaros ameliorated the response of MM cells to LPS in vitro and in vivo. Consistent with these findings, infection-triggered progression was not observed in MM patients under treatment with Ikaros-degrading immunomodulatory drugs. The LPS-CD180/MD-1 pathway represents a novel mechanism of disease progression and is a therapeutic target for prolonging survival in MM patients.