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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1846-1854. Prepublished online as a Blood First Edition Paper on November 20, 2003; DOI 10.1182/blood-2003-08-2836. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-08-2836v1 103/5/1846    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 Mone, A. P. Articles by Byrd, J. C. Search for Related Content PubMed PubMed Citation Articles by Mone, A. P. Articles by Byrd, J. C. Related Collections Immunobiology Neoplasia Apoptosis Signal Transduction Immunotherapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Hu1D10 induces apoptosis concurrent with activation of the AKT survival pathway in human chronic lymphocytic leukemia cells Andrew P. Mone, Peng Huang, Helene Pelicano, Carolyn M. Cheney, Jennifer M. Green, J. Yun Tso, Amy J. Johnson, Sara Jefferson, Thomas S. Lin, and John C. Byrd From the Division of Hematology-Oncology, The Ohio State University, Columbus; Department of Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston; and Protein Design Labs Inc, Fremont, CA. The 1D10 antigen is the target for Hu1D10 (apolizumab), a humanized HLA-DR -chain–specific antibody that is currently in clinical trials for hematologic malignancies. We demonstrate that Hu1D10 induces caspase-independent apoptosis following secondary cross-linking in primary chronic lymphocytic leukemia (CLL) cells. Generation of reactive oxygen species (ROS) and signal transduction, as evidenced by phosphorylation of Syk and AKT, were noted. The source of the Hu1D10-induced ROS was examined using the Raji lymphoblastic cell line with engineered defects in the mitochondrial respiratory chain. Hu1D10 treatment of clones with deficient mitochondrial respiration produced ROS suggesting a cytoplasmic source. Administration of ROS scavengers to primary CLL cells prior to Hu1D10 treatment diminished AKT activation. Treatment with Hu1D10 and the phosphatidylinositol 3-kinase inhibitor LY294002 demonstrated in vitro synergy with enhanced apoptosis. In conjunction with an ongoing clinical trial, blood samples were collected following intravenous infusion of Hu1D10 and analyzed for phosphorylation of AKT. Two of 3 patient samples showed a sustained increase in AKT phosphorylation following Hu1D10 administration. These data suggest that Hu1D10 ligation in CLL cells induces death and survival signals for which combination therapies may be designed to greatly enhance efficiency of both Hu1D10 and other class II antibodies in development. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Monoclonal antibodies in the treatment of chronic lymphocytic leukemia: if only it were simple Emili Montserrat Blood 2004 103: 1567-1568. [Full Text] [PDF] This article has been cited by other articles: R. Lapalombella, B. Yu, G. Triantafillou, Q. Liu, J. P. Butchar, G. Lozanski, A. Ramanunni, L. L. Smith, W. Blum, L. Andritsos, et al. 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