Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma
- Katrina K. Hoyer*,
- Samuel W. French*,
- Devin E. Turner*,
- Mai T. N. Nguyen*,
- Mathilde Renard*,
- Cindy S. Malone†,
- Sonja Knoetig‡,
- Chen-Feng Qi‡,
- Thomas T. Su§,
- Hilde Cheroutre¶,
- Randolph Wall†,§,∥,
- David J. Rawlings**,
- Herbert C. MorseIII‡, and
- Michael A. Teitell*,§,∥,††,‡‡
- Departments of *Pathology and Laboratory Medicine and† Microbiology and Immunology, §Molecular Biology Institute, ∥Jonsson Comprehensive Cancer Center, and ††AIDS Institute, University of California School of Medicine, Los Angeles, CA 90095; ‡Laboratory of Immunopathology, National Institutes of Health, Bethesda, MD 20892; ¶Developmental Immunology, La Jolla Institute of Allergy and Immunology, San Diego, CA 92121; and **Pediatrics and Immunology, University of Washington School of Medicine, Seattle, WA 98195
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Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved August 22, 2002 (received for review July 8, 2002)
Abstract
The TCL1 protooncogene is overexpressed in many mature B cell lymphomas, especially from AIDS patients. To determine whether aberrant expression promotes B cell transformation, we generated a murine model in which a TCL1 transgene was overexpressed at similar levels in both B and T cells. Strikingly, transgenic mice developed Burkitt-like lymphoma (BLL) and diffuse large B cell lymphoma (DLBCL) with attendant Bcl-6 expression and mutated JH gene segments at a very high penetrance beginning at 4 months of age. In contrast, only one mouse developed a T cell malignancy at 15 months, consistent with a longer latency for transformation of T cells by TCL1. Activation of premalignant splenic B cells by means of B cell antigen receptor (BCR) engagement resulted in significantly increased proliferation and augmented AKT-dependent signaling, including increased S6 ribosomal protein phosphorylation. Transgenic spleen cells also survived longer than wild-type spleen cells in long-term culture. Together these data demonstrate that TCL1 is a powerful oncogene that, when overexpressed in both B and T cells, predominantly yields mature B cell lymphomas.
Footnotes
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↵ ‡‡ To whom correspondence should be addressed at: Department of Pathology and Laboratory Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail: mteitell{at}ucla.edu.
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This paper was submitted directly (Track II) to the PNAS office.
- Abbreviations:
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DLBCL, diffuse large B cell lymphoma
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BLL, Burkitt-like lymphoma
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TCR, T cell antigen receptor
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BCR, B cell antigen receptor
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GC, germinal center
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NHL, non-Hodgkin lymphoma
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BM, bone marrow
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LPS, lipopolysaccharide
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- Copyright © 2002, The National Academy of Sciences
