Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma.
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 J(H) 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.
Hoyer
Katrina K
KK
Department of Pathology and Laboratory Medicine, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, and AIDS Institute, University of California School of Medicine, Los Angeles, CA 90095, USA.
French
Samuel W
SW
Turner
Devin E
DE
Nguyen
Mai T N
MT
Renard
Mathilde
M
Malone
Cindy S
CS
Knoetig
Sonja
S
Qi
Chen-Feng
CF
Su
Thomas T
TT
Cheroutre
Hilde
H
Wall
Randolph
R
Rawlings
David J
DJ
Morse
Herbert C
HC
Teitell
Michael A
MA
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000378:metabolism*; D002455:Cell Division; D005260:Female; D015870:Gene Expression; D008218:Lymphocytosis / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism*; D008232:Lymphoproliferative Disorders / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014170:Transformation, Genetic
D011518:Proto-Oncogene Proteins; D038601:Ribosomal Protein S6; C490393:Tcl1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt