RRC ID 50076
Author Kikuchi J, Kuroda Y, Koyama D, Osada N, Izumi T, Yasui H, Kawase T, Ichinohe T, Furukawa Y.
Title Myeloma Cells Are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex, Which Senses Lipopolysaccharide.
Journal Cancer Res
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.
Volume 78(7)
Pages 1766-1778
Published 2018-4-1
DOI 10.1158/0008-5472.CAN-17-2446
PII 0008-5472.CAN-17-2446
PMID 29363546
MeSH Animals Antibodies / immunology Antigens, CD / genetics Antigens, CD / immunology Antigens, CD / metabolism* Antigens, Surface / metabolism* Bone Marrow / pathology* Bone Marrow Cells / metabolism* Cell Adhesion / genetics Cell Hypoxia / genetics Cell Line, Tumor Cell Proliferation / physiology Cellular Microenvironment / physiology Humans Ikaros Transcription Factor / antagonists & inhibitors Ikaros Transcription Factor / genetics Immunologic Factors / pharmacology Lenalidomide / pharmacology Lipopolysaccharides / metabolism* Membrane Glycoproteins / metabolism* Mesenchymal Stem Cells / metabolism* Mice Mice, Inbred NOD Mice, SCID Multiple Myeloma / pathology* Neoplasm Transplantation Promoter Regions, Genetic / genetics Transcriptional Activation / genetics Transplantation, Heterologous
IF 9.727
Times Cited 6
DNA material CSII-CMV-MCS-IRES2-Venus (RDB04383).