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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1309-1317. Prepublished online as a Blood First Edition Paper on October 18, 2007; DOI 10.1182/blood-2007-03-078535. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-03-078535v1 111/3/1309    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shi, J. Articles by van Rhee, F. Search for Related Content PubMed PubMed Citation Articles by Shi, J. Articles by van Rhee, F. Related Collections Immunobiology Neoplasia Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell–mediated lysis of myeloma Jumei Shi1, Guido J. Tricot1, Tarun K. Garg1, Priyangi A. Malaviarachchi1, Susann M. Szmania1, Rachel E. Kellum1, Brian Storrie2, Arend Mulder3, John D. Shaughnessy, Jr1, Bart Barlogie1, and Frits van Rhee1 1 Myeloma Institute for Research and Therapy and 2 Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock; and 3 Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands Human leukocyte antigen class I molecules expressed by tumor cells play a central role in the regulation of natural killer (NK) cell–mediated immune responses. The proteasome inhibitor bortezomib has demonstrated significant activity in multiple myeloma (MM). We hypothesized that treatment of MM with bortezomib results in the reduction of cell-surface expression of class I and thereby sensitizes MM to NK cell–mediated lysis. Here we report that bortezomib down-regulates class I in a time- and dose-dependent fashion on all MM cell lines and patient MM cells tested. Downregulation of class I can also be induced in vivo after a single dose of 1.0 mg/m2 bortezomib. Bortezomib significantly enhances the sensitivity of patient myeloma to allogeneic and autologous NK cell–mediated lysis. Further, the level of decrease in class I expression correlates with increased susceptibility to lysis by NK cells. Clinically relevant bortezomib concentrations do not affect NK-cell function. Our findings have clear therapeutic implications for MM and other NK cell–sensitive malignancies in the context of both allogeneic and autologous adoptively transferred NK cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Basler, C. Lauer, U. Beck, and M. Groettrup The Proteasome Inhibitor Bortezomib Enhances the Susceptibility to Viral Infection J. Immunol., November 15, 2009; 183(10): 6145 - 6150. [Abstract] [Full Text] [PDF] F. van Rhee, S. M. Szmania, M. Dillon, A. M. van Abbema, X. Li, M. K. Stone, T. K. Garg, J. Shi, A. M. Moreno-Bost, R. Yun, et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma Mol. Cancer Ther., September 1, 2009; 8(9): 2616 - 2624. [Abstract] [Full Text] [PDF] D. J. Anstee Red cell genotyping and the future of pretransfusion testing Blood, July 9, 2009; 114(2): 248 - 256. [Abstract] [Full Text] [PDF] H. Fujisaki, H. Kakuda, N. Shimasaki, C. Imai, J. Ma, T. Lockey, P. Eldridge, W. H. Leung, and D. Campana Expansion of Highly Cytotoxic Human Natural Killer Cells for Cancer Cell Therapy Cancer Res., May 1, 2009; 69(9): 4010 - 4017. [Abstract] [Full Text] [PDF] A. Soriani, A. Zingoni, C. Cerboni, M. L. Iannitto, M. R. Ricciardi, V. Di Gialleonardo, M. Cippitelli, C. Fionda, M. T. Petrucci, A. Guarini, et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype Blood, April 9, 2009; 113(15): 3503 - 3511. [Abstract] [Full Text] [PDF] X. Wang, A. Ottosson, C. Ji, X. Feng, M. Nordenskjold, J.-I. Henter, B. Fadeel, and C. Zheng Proteasome inhibition induces apoptosis in primary human natural killer cells and suppresses NKp46-mediated cytotoxicity Haematologica, April 1, 2009; 94(4): 470 - 478. [Abstract] [Full Text] [PDF] A. S. M. Yong, K. Keyvanfar, N. Hensel, R. Eniafe, B. N. Savani, M. Berg, A. Lundqvist, S. Adams, E. M. Sloand, J. M. Goldman, et al. Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib Blood, January 22, 2009; 113(4): 875 - 882. [Abstract] [Full Text] [PDF]

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