SEARCH:   Advanced

Blood, 12 March 2009, Vol. 113, No. 11, pp. 2478-2487. Prepublished online as a Blood First Edition Paper on January 15, 2009; DOI 10.1182/blood-2008-05-156943. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-05-156943v1 113/11/2478    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 Frank, M. J. Articles by Teitell, M. A. Search for Related Content PubMed PubMed Citation Articles by Frank, M. J. Articles by Teitell, M. A. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas Matthew J. Frank1, David W. Dawson1,2, Steven J. Bensinger1,3, Jason S. Hong1, Wendy M. Knosp4, Lizhong Xu5, Cynthia E. Balatoni1, Eric L. Allen1, Rhine R. Shen1, Dafna Bar-Sagi5, Gail R. Martin4, and Michael A. Teitell1,2,6 1 Department of Pathology and Laboratory Medicine and 2 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, and 3 Institute for Molecular Medicine, University of California–Los Angeles; 4 Department of Anatomy and Program in Developmental Biology, University of California at San Francisco; 5 Department of Biochemistry, New York University School of Medicine, NY; and 6 Molecular Biology Institute, NDC Center for Cell Control, Broad Institute for Regenerative Medicine and Stem Cell Research, and California NanoSystems Institute, University of California–Los Angeles B-cell lymphoma is the most common immune system malignancy. TCL1 transgenic mice (TCL1-tg), in which TCL1 is ectopically expressed in mature lymphocytes, develop multiple B- and T-cell leukemia and lymphoma subtypes, supporting an oncogenic role for TCL1 that probably involves AKT and MAPK-ERK signaling pathway augmentation. Additional, largely unknown genetic and epigenetic alterations cooperate with TCL1 during lymphoma progression. We examined DNA methylation patterns in TCL1-tg B-cell tumors to discover tumor-associated epigenetic changes, and identified hypermethylation of sprouty2 (Spry2). Sprouty proteins are context-dependent negative or positive regulators of MAPK-ERK pathway signaling, but their role(s) in B-cell physiology or pathology are unknown. Here we show that repression of Spry2 expression in TCL1-tg mouse and human B-cell lymphomas and cell lines is associated with dense DNA hypermethylation and was reversed by inhibition of DNA methylation. Spry2 expression was induced in normal splenic B cells by CD40/B-cell receptor costimulation and regulated a negative feedback loop that repressed MAPK-ERK signaling and decreased B-cell viability. Conversely, loss of Spry2 function hyperactivated MAPK-ERK signaling and caused increased B-cell proliferation. Combined, these results implicate epigenetic silencing of Spry2 expression in B lymphoma progression and suggest it as a companion lesion to ectopic TCL1 expression in enhancing MAPK-ERK pathway signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020