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Blood, 1 June 2007, Vol. 109, No. 11, pp. 5002-5010.
Prepublished online as a Blood First Edition Paper on February 20, 2007; DOI 10.1182/blood-2006-03-012542.
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Submitted March 24, 2006
Accepted January 4, 2007
CD28-mediated regulation of multiple myeloma cell proliferation and survival
Nizar Jacques Bahlis, Anne M. King, Despina Kolonias, Louise M Carlson, Hong Yu Liu, Mohamad A Hussein, Howard R Terebelo, Gerald E Byrne Jr, Bruce L Levine, Lawrence H Boise, and Kelvin P Lee*
Dept of Microbiology & Immunology, University of Miami School of Medicine, Miami, FL
University of Miami Sylvester Comprehensive Cancer Center, Miami, FL
USF College of Medicine, and H. Lee Moffitt Cancer & Research Institute, Tampa, FL
Providence Hospital, Southfield, MI
Dept of Pathology, University of Miami School of Medicine, Miami, FL
Dept of Pathology & Laboratory Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA
Dept of Microbiology & Immunology, Univeristy of Miami School of Medicine, Miami, FL
Division of Hematology and Oncology, Dept of Medicine, University of Miami School of Medicine, Miami, FL
* Corresponding author; email: kelvin.lee{at}roswellpark.org.
Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown - due in large part to the complexity of the bone marrow microenvironment itself. The T cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in multiple myeloma correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NF B, suppresses MM cell proliferation and protects against serum starvation and dexamethasone-induced cell death. Coculture with dendritic cells (DC) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DC appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma:DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of multiple myeloma.
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