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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4309-4318.
Prepublished online as a Blood First Edition Paper on February 4, 2009; DOI 10.1182/blood-2008-10-183772.
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Submitted October 16, 2008
Accepted January 18, 2009
CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells
Yu-Tzu Tai*, Ender Soydan, Weihua Song, Mariateresa Fulciniti, Kihyun Kim, Fangxin Hong, Xian-Feng Li, Peter Burger, Matthew J. Rumizen, Sabikun Nahar, Klaus Podar, Teru Hideshima, Nikhil C. Munshi, Giovanni Tonon, Ruben D. Carrasco, Daniel E.H. Afar, and Kenneth C. Anderson
The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Boston, MA, United States
Division of Hematology/Oncology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea, Republic of
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA, United States
Functional Genomics of Cancer Unit, Division of Oncology, Instituto Scientifico San Raffaele, Milano, Italy
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
Oncology Programs, Facet Biotech, Redwood City, CA, United States
* Corresponding author; email: yu-tzu_tai{at}dfci.harvard.edu.
The cell surface glycoprotein CS1 is highly expressed on tumor cells from the majority of multiple myeloma (MM) patients (>95%) 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 to control MM cells, associated with earlier activation of caspases, PARP, 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  7/ E-mediated myeloma adhesion to BMSCs, and -VEGF-induced BM 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.
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