Involvement of innate immunity in the expansion of multiple myeloma cells and therapeutic intervention with lenalidomide

Abstract

Multiple myeloma (MM) cells acquire dormancy and drug resistance via their interaction with bone marrow stroma cells (BMSCs) in a hypoxic microenvironment. In this study, we found a positive expression of CD180/MD-1 complex (a non-canonical toll-like receptor) on MM cells, which was markedly up-regulated under adherent and/or hypoxic conditions. Bacterial lipopolysaccharide (LPS) enhanced the growth of MM cells via the activation of MAP kinases, an effect which showed a positive correlation with the expression levels of CD180. LPS administration significantly increased CD180/CD138 double-positive cell number in a murine xenograft model after the inoculation of MM cells directly attached to BMSCs. Notably, the shRNA-mediated knockdown of CD180 terminated the LPS response in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene, whose transcription was activated via cell adhesion and hypoxia by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros with lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner in vitro and in vivo. CD180/MD-1 pathway may represent a novel mechanism for the regulation of the growth of MM cells in BM milieu and may serve as a therapeutic target to prevent the regrowth of dormant MM cells.