Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL
Abstract
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-κB 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-κB 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-κB activity and inhibiting AP-1.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- December 2008
- DOI:
- 10.1073/pnas.0810965105
- Bibcode:
- 2008PNAS..10519643P
- Keywords:
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- Biological Sciences:Biochemistry