CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells.
CS1 is highly expressed on tumor cells from the majority of multiple myeloma (MM) patients regardless of cytogenetic abnormalities or response to current treatments. Furthermore, CS1 is detected in MM patient sera and correlates with active disease. However, its contribution to MM pathophysiology is undefined. We here show that CS1 knockdown using lentiviral short-interfering RNA decreased phosphorylation of ERK1/2, AKT, and STAT3, suggesting that CS1 induces central growth and survival signaling pathways in MM cells. Serum deprivation markedly blocked survival at earlier time points in CS1 knockdown compared with control MM cells, associated with earlier activation of caspases, poly(ADP-ribose) polymerase, and proapoptotic proteins BNIP3 and BIK. CS1 knockdown further delayed development of MM tumor and prolonged survival in mice. Conversely, CS1 overexpression promoted myeloma cell growth and survival by significantly increasing myeloma adhesion to bone marrow stromal cells (BMSCs) and enhancing myeloma colony formation in semisolid culture. Moreover, CS1 increased c-maf-targeted cyclin D2-dependent proliferation, -integrin beta7/alphaE-mediated myeloma adhesion to BMSCs, and -vascular endothelial growth factor-induced bone marrow angiogenesis in vivo. These studies provide direct evidence of the role of CS1 in myeloma pathogenesis, define molecular mechanisms regulating its effects, and further support novel therapies targeting CS1 in MM.
Tai
Yu-Tzu
YT
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. yu-tzu_tai@dfci.harvard.edu
Soydan
Ender
E
Song
Weihua
W
Fulciniti
Mariateresa
M
Kim
Kihyun
K
Hong
Fangxin
F
Li
Xian-Feng
XF
Burger
Peter
P
Rumizen
Matthew J
MJ
Nahar
Sabikun
S
Podar
Klaus
K
Hideshima
Teru
T
Munshi
Nikhil C
NC
Tonon
Giovanni
G
Carrasco
Ruben D
RD
Afar
Daniel E H
DE
Anderson
Kenneth C
KC
D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology*; D002462:Cell Membrane; D049109:Cell Proliferation; D002470:Cell Survival; D003114:Colony-Forming Units Assay; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D016086:Lentivirus / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D016895:Culture Media, Serum-Free; C482653:ITPRID2 protein, human; C495607:MAF protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D051257:Proto-Oncogene Proteins c-maf; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3