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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.
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Submitted February 2, 2006
Accepted May 8, 2006
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*
Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles
Howard Hughes Institute and Children's Hospital, Harvard Medical School, Boston, MA
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, NIH, MD, USA
Howard Hughes Medical Institute and Children's Hospital, Harvard Medical School, Boston, MA, USA
* Corresponding author; email: mteitell{at}ucla.edu.
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 to 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 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 OCA-B-deficient background to yield mice incapable of forming GC. Spectral karyotype analyses showed that GC lymphomas from TCL1-tg mice exhibit recurrent chromosome translocations and trisomy15, 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.
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