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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1346-1352. Prepublished online as a Blood First Edition Paper on April 25, 2006; DOI 10.1182/blood-2005-12-007971. This Article Full Text (PDF) All Versions of this Article: blood-2005-12-007971v1 108/4/1346    most recent Alert me when this article is cited Alert me if a correction is posted 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 Menoret, E. Articles by Pellat-Deceunynck, C. Search for Related Content PubMed PubMed Citation Articles by Menoret, E. Articles by Pellat-Deceunynck, C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 21, 2005 Accepted April 5, 2006 Mcl-1L cleavage is involved in TRAIL-R1 and TRAIL-R2 mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAb in myeloma cells Emmanuelle Menoret, Patricia Gomez-Bougie, Alexandrine Geffroy-Luseau, Sylvanne Daniels, Philippe Moreau, Steven Le Gouill, Jean-Luc Harousseau, Regis Bataille, Martine Amiot, and Catherine Pellat-Deceunynck* INSERM, U601; Universite de Nantes, Nantes Atlantique Universites, UFR Medecine, Nantes, France Universite de Nantes,Nantes Atlantique Universites,UFR Medecine et Techniques Medicales, France * Corresponding author; email: cpellat{at}nantes.inserm.fr. We evaluated the ability of two human mAbs directed against TRAILR1 (HGS-ETR1) and TRAILR2 (HGS-ETR2) to kill human myeloma cells. HGS-ETR1 and HGS-ETR2 mAbs killed 15 and 9 human myeloma cell lines, HMCL (n=22), respectively. Killing of HMCL was not prevented by IL-6, the major survival and growth factor for these HMCL. Killing induced by either HGS-ETR1 or ETR2 was correlated with cleavage of Mcl-1L, a major molecule for myeloma survival. Mcl-1L cleavage and Anti-TRAILR HMCL killing were dependent on caspase activation. Kinetic studies showed that cleavage of Mcl-1L occurred very early (<1 hr) and became drastic once caspase 3 was activated. Our data show that both the extrinsic (caspase 8, Bid) and intrinsic (caspase 9) pathways are activated by anti-TRAIL mAb. Finally, we show that HGS-ETR1 mAb, and to a less extend HGS-ETR2, were able to induce killing of primary myeloma cells. Of note, HGS-ETR1 mAb was able to induce cell death of medullary and extramedullary myeloma cells collected from patients at relapse. Taken together our data clearly support clinical trials of anti-TRAILR1 mAb in MM, especially for patients at relapse, at the time of drug resistance. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Chiron, C. Pellat-Deceunynck, M. Maillasson, R. Bataille, and G. Jego Phosphorothioate-Modified TLR9 Ligands Protect Cancer Cells against TRAIL-Induced Apoptosis J. Immunol., October 1, 2009; 183(7): 4371 - 4377. [Abstract] [Full Text] [PDF] S. Leong, R. B. Cohen, D. L. Gustafson, C. J. Langer, D. R. Camidge, K. Padavic, L. Gore, M. Smith, L. Q. Chow, M. von Mehren, et al. Mapatumumab, an Antibody Targeting TRAIL-R1, in Combination With Paclitaxel and Carboplatin in Patients With Advanced Solid Malignancies: Results of a Phase I and Pharmacokinetic Study J. Clin. Oncol., September 10, 2009; 27(26): 4413 - 4421. [Abstract] [Full Text] [PDF] D. Chiron, C. Pellat-Deceunynck, M. Amiot, R. Bataille, and G. Jego TLR3 Ligand Induces NF-{kappa}B Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-{alpha} Production J. Immunol., April 1, 2009; 182(7): 4471 - 4478. [Abstract] [Full Text] [PDF] T. A. Luster, J. A. Carrell, K. McCormick, D. Sun, and R. Humphreys Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib Mol. Cancer Ther., February 1, 2009; 8(2): 292 - 302. [Abstract] [Full Text] [PDF] G. Desplanques, N. Giuliani, R. Delsignore, V. Rizzoli, R. Bataille, and S. Barille-Nion Impact of XIAP protein levels on the survival of myeloma cells Haematologica, January 1, 2009; 94(1): 87 - 93. [Abstract] [Full Text] [PDF] E. Menoret, S. Surget, P. Gomez-Bougie, R. Bataille, M. Amiot, and C. Pellat-Deceunynck Agonist Anti-TRAILR1 Human Mab, Hgs-ETR1, Induces Myeloma Cell Death Mainly through the Intrinsic Pathway of Apoptosis. Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 1713 - 1713. [Abstract] A. Ashkenazi, P. Holland, and S. G. Eckhardt Ligand-Based Targeting of Apoptosis in Cancer: The Potential of Recombinant Human Apoptosis Ligand 2/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (rhApo2L/TRAIL) J. Clin. Oncol., July 20, 2008; 26(21): 3621 - 3630. [Abstract] [Full Text] [PDF] A. Geffroy-Luseau, G. Jego, R. Bataille, L. Campion, and C. Pellat-Deceunynck Osteoclasts support the survival of human plasma cells in vitro Int. Immunol., June 1, 2008; 20(6): 775 - 782. [Abstract] [Full Text] [PDF] M. Romagnoli, G. Desplanques, S. Maiga, S. Legouill, M. Dreano, R. Bataille, and S. Barille-Nion Canonical Nuclear Factor {kappa}B Pathway Inhibition Blocks Myeloma Cell Growth and Induces Apoptosis in Strong Synergy with TRAIL Clin. Cancer Res., October 15, 2007; 13(20): 6010 - 6018. [Abstract] [Full Text] [PDF]

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