SEARCH:   Advanced

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. This Article Full Text Full Text (PDF) Erratum (v114,p2852) All Versions of this Article: blood-2008-10-183772v1 113/18/4309    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tai, Y.-T. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Tai, Y.-T. Articles by Anderson, K. C. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf–mediated interactions with bone marrow stromal cells Yu-Tzu Tai1, Ender Soydan1, Weihua Song1, Mariateresa Fulciniti1, Kihyun Kim1,2, Fangxin Hong3, Xian-Feng Li1, Peter Burger1, Matthew J. Rumizen1, Sabikun Nahar1, Klaus Podar1, Teru Hideshima1, Nikhil C. Munshi1, Giovanni Tonon1,4, Ruben D. Carrasco1,5, Daniel E. H. Afar6, and Kenneth C. Anderson1 1 LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 2 Division of Hematology/Oncology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; 3 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA; 4 Functional Genomics of Cancer Unit, Division of Oncology, Istituto Scientifico San Raffaele, Milano, Italy; 5 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and 6 Oncology Programs, Facet Biotech, Redwood City, CA 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 β7/E-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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020