Abstract
Multiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a noncanonical lipopolysaccharide (LPS) receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Bacterial LPS and anti-CD180 antibody, but not other Toll-like receptor ligands, enhanced the growth of MM cells via activation of MAP kinases ERK and JNK in positive correlation with expression levels of CD180. Administration of LPS significantly increased the number of CD180/CD138 double-positive cells in a murine xenograft model when MM cells were inoculated with direct attachment to BMSC. Knockdown of CD180 canceled the LPS response in vitro and in vivo Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene. Both cell adhesion and hypoxia activated transcription of the CD180 gene by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros by the immunomodulatory drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner in vitro and in vivo Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells.Significance: This study describes a novel mechanism by which myeloma cells are regulated in the bone marrow, where drug resistance and dormancy can evolve after treatment, with potential therapeutic implications for treating this often untreatable blood cancer. Cancer Res; 78(7); 1766-78. ©2018 AACR.
Highlights
Multiple myeloma (MM) is characterized by deregulated growth of plasma cells (PC), terminally differentiated B-lymphocytes, in the bone marrow (BM)
We found a significant increase in transcription and DNA copy numbers of the CD180 gene in MM cells relative to normal PCs www.aacrjournals.org
Immunofluorescent staining revealed the activation of Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), which coincided with CD19 but not Toll-like receptor 4 (TLR4) expression, in CD180-positive MM cells after stimulation with either LPS or anti-CD180 antibody (Fig. 2D/E; Supplementary Fig. S4G). These results strongly suggest that LPS enhances the growth of MM cells via the CD180/MD-1 pathway by the aid of CD19 [9, 24], which was expressed on dormant MM cells via the interaction with bone marrow stroma cells (BMSC) [25, 26]
Summary
Multiple myeloma (MM) is characterized by deregulated growth of plasma cells (PC), terminally differentiated B-lymphocytes, in the bone marrow (BM). Initial treatments with proteasome inhibitors and/or immunomodulatory drugs (IMiD) significantly increased the remission rate of MM; MM is still one of the most intractable malignancies due to a high incidence of relapse [1, 2]. It is widely accepted that relapse stems from dormant and highly drug-resistant clones in the MM compartment. Drugresistant clones are kept dormant via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment [3,4,5,6]. Elucidation of the mechanisms underlying the regrowth of dormant clones may prolong remission and improve the survival of MM patients.
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