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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1991-1998. Prepublished online as a Blood First Edition Paper on May 25, 2006; DOI 10.1182/blood-2006-02-001354. This Article Full Text Full Text (PDF) Supplemental Methods and Tables Supplemental Figures All Versions of this Article: blood-2006-02-001354v1 108/6/1991    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 Shen, R. R. Articles by Teitell, M. A. Search for Related Content PubMed PubMed Citation Articles by Shen, R. R. Articles by Teitell, M. A. Related Collections Immunobiology Neoplasia Oncogenes and Tumor Suppressors Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Dysregulated TCL1 requires the germinal center and genome instability for mature B-cell transformation Rhine R. Shen, David O. Ferguson, Mathilde Renard, Katrina K. Hoyer, Unkyu Kim, Xingpei Hao, Frederick W. Alt, Robert G. Roeder, Herbert C. Morse, III, and Michael A. Teitell From the Departments of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center and Molecular Biology Institute, David Geffen School of Medicine at University of California at Los Angeles, CA; Howard Hughes Medical Institute and Children's Hospital, Center for Blood Research and Department of Genetics, Harvard Medical School, Boston, MA; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY; and Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Rockville, MD. Most lymphomas arise by transformation of germinal center (GC) B cells. TCL1, a proto-oncogene first recognized for its role in T-cell transformation, also induces GC B-cell malignancies when dysregulated in pEµ-B29-TCL1 transgenic (TCL1-tg) mice. Clonal B-cell lymphomas develop from polyclonal populations with latencies of 4 months or more, suggesting that secondary genetic events are required for full transformation. The goals of this study were to determine the GC-related effects of TCL1 dysregulation that contribute to tumor initiation and to identify companion genetic alterations in tumors that function in disease progression. We report that compared with wild-type (WT) cells, B cells from TCL1-tg mice activated in a manner resembling a T-dependent GC reaction show enhanced resistance to FAS-mediated apoptosis with CD40 stimulation, independent of a B-cell antigen receptor (BCR) rescue signal. Mitogenic stimulation of TCL1-tg B cells also resulted in increased expression of Aicda. These GC-related enhancements in survival and Aicda expression could underlie B-cell transformation. Supporting this notion, no B-cell lymphomas developed for 20 months when TCL1-tg mice were crossed onto an Oct coactivator from B cell (OCA-B)–deficient background to yield mice incapable of forming GCs. Spectral karyotype analyses showed that GC lymphomas from TCL1-tg mice exhibit recurrent chromosome translocations and trisomy 15, with corresponding MYC overexpression. We conclude that pEµ-B29-TCL1 transgenic B cells primed for transformation must experience the GC environment and, for at least some, develop genome instability to become fully malignant. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: TCL1-induced germinal center B lymphomas in mice Siegfried Janz Blood 2006 108: 1791-1792. [Full Text] [PDF] This article has been cited by other articles: M. J. Frank, D. W. Dawson, S. J. Bensinger, J. S. Hong, W. M. Knosp, L. Xu, C. E. Balatoni, E. L. Allen, R. R. Shen, D. Bar-Sagi, et al. Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas Blood, March 12, 2009; 113(11): 2478 - 2487. [Abstract] [Full Text] [PDF] G. Despouy, M. Joiner, E. Le Toriellec, R. Weil, and M. H. Stern The TCL1 oncoprotein inhibits activation-induced cell death by impairing PKC{theta} and ERK pathways Blood, December 15, 2007; 110(13): 4406 - 4416. [Abstract] [Full Text] [PDF] A. I. Kuraishy, S. W. French, M. Sherman, M. Herling, D. Jones, R. Wall, and M. A. Teitell TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation PNAS, June 12, 2007; 104(24): 10175 - 10180. [Abstract] [Full Text] [PDF] F. Boccellato, E. Anastasiadou, P. Rosato, B. Kempkes, L. Frati, A. Faggioni, and P. Trivedi EBNA2 Interferes with the Germinal Center Phenotype by Downregulating BCL6 and TCL1 in Non-Hodgkin's Lymphoma Cells J. Virol., March 1, 2007; 81(5): 2274 - 2282. 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