Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL.

B cell chronic lymphocytic leukemia (B-CLL) is the most common human leukemia. Deregulation of the T cell leukemia/lymphoma 1 (TCL1) oncogene in mouse B cells causes a CD5-positive leukemia similar to aggressive human B-CLLs. To examine the mechanisms by which Tcl1 protein exerts oncogenic activity in B cells, we investigated ...
the effect of Tcl1 expression on NF-kappaB and activator protein 1 (AP-1) activity. We found that Tcl1 physically interacts with c-Jun, JunB, and c-Fos and inhibits AP-1 transcriptional activity. Additionally, Tcl1 activates NF-kappaB by physically interacting with p300/CREB binding protein. We then sequenced the TCL1 gene in 600 B-CLL samples and found 2 heterozygous mutations: T38I and R52H. Importantly, both mutants showed gain of function as AP-1 inhibitors. The results indicate that Tcl1 overexpression causes B-CLL by directly enhancing NF-kappaB activity and inhibiting AP-1.
Mesh Terms:
Animals, Apoptosis, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, Mutation, NF-kappa B, NIH 3T3 Cells, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, Transcription Factor AP-1, p300-CBP Transcription Factors
Proc. Natl. Acad. Sci. U.S.A.
Date: Dec. 16, 2008
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