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

Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19643-8. doi: 10.1073/pnas.0810965105. Epub 2008 Dec 8.

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-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Mice
  • Mutation
  • NF-kappa B / metabolism
  • NIH 3T3 Cells
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • p300-CBP Transcription Factors / metabolism

Substances

  • NF-kappa B
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-jun
  • TCL1A protein, human
  • Transcription Factor AP-1
  • p300-CBP Transcription Factors