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Blood, 15 October 2007, Vol. 110, No. 8, pp. 3028-3035. Prepublished online as a Blood First Edition Paper on July 20, 2007; DOI 10.1182/blood-2007-06-094417. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-06-094417v1 110/8/3028    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 Yang, J. Articles by Yi, Q. Search for Related Content PubMed PubMed Citation Articles by Yang, J. Articles by Yi, Q. Related Collections Immunobiology Neoplasia Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Anti–ß2-microglobulin monoclonal antibodies induce apoptosis in myeloma cells by recruiting MHC class I to and excluding growth and survival cytokine receptors from lipid rafts Jing Yang1, Xiang Zhang1, Ji Wang1, Jianfei Qian1, Liang Zhang1, Michael Wang1, Larry W. Kwak1, and Qing Yi1 1 Department of Lymphoma and Myeloma, Division of Cancer Medicine, and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX We recently showed that monoclonal antibodies (mAbs) against ß2-microglobulin (ß2M) have a remarkably strong apoptotic effect on myeloma cells. The mAbs induced apoptosis by recruiting major histocompatibility complex (MHC) class I to lipid rafts, activated c-Jun N-terminal kinase (JNK), and inhibited phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal–regulated kinase (ERK) pathways. Growth and survival cytokines such as interleukin-6 (IL-6) and insulin-like growth factor-I (IGF-I), which could protect myeloma cells from dexamethasone-induced apoptosis, did not affect mAb-mediated cell death. This study was undertaken to elucidate the mechanisms underlying anti-ß2M mAb–induced PI3K/Akt and ERK inhibition and the inability of IL-6 and IGF-I to protect myeloma cells from mAb-induced apoptosis. We focused on lipid rafts and confirmed that these membrane microdomains are required for IL-6 and IGF-I signaling. By recruiting MHC class I into lipid rafts, anti-ß2M mAbs excluded IL-6 and IGF-I receptors and their substrates from the rafts. The mAbs not only redistributed the receptors in cell membrane, but also abrogated IL-6– or IGF-I–mediated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), PI3K/Akt, and Ras/Raf/ERK pathway signaling, which are otherwise constitutively activated in myeloma cells. Thus, this study further defines the tumoricidal mechanism of the mAbs and provides strong evidence to support the potential of these mAbs as therapeutic agents for myeloma. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Death by rafting Suzanne Lentzsch Blood 2007 110: 2791-2792. [Full Text] [PDF]

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