AP-1 elements and TCL1 protein regulate expression of the gene encoding protein tyrosine phosphatase PTPROt in leukemia

Blood. 2011 Dec 1;118(23):6132-40. doi: 10.1182/blood-2011-01-323147. Epub 2011 Oct 14.


We previously demonstrated that the gene encoding PTPROt, the truncated form of protein tyrosine phosphatase receptor type O expressed predominantly in hematopoietic cells, is a candidate tumor suppressor and is down-regulated in chronic lymphocytic leukemia (CLL). Here, we show that PTPROt expression is significantly reduced in CD19(+) spleen B cells from Eμ-T cell leukemia 1 (TCL1) transgenic mice relative to the wild-type mice. Strikingly, as much as a 60% decrease in PTPROt expression occurs at 7 weeks independently of promoter methylation. To elucidate the potential mechanism for this early suppression of PTPROt in these mice, we explored the role of activating protein-1 (AP-1) in its expression. We first demonstrate that AP-1 activation by 12-O-tetradecanoylphorbol-13-acetate induces PTPROt expression with concurrent recruitment of c-fos and c-jun to its promoter. The PTPROt promoter is also responsive to over- and underexpression of AP-1, confirming the role of AP-1 in PTPROt expression. Next, we demonstrate that TCL1 can repress the PTPROt promoter by altering c-fos expression and c-jun activation state. Finally, using primary CLL cells we have shown an inverse relationship between TCL1 and PTPROt expression. These findings further substantiate the role of TCL1 in PTPROt suppression and its importance in the pathogenesis of CLL.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Down-Regulation / genetics
  • Gene Expression Regulation, Leukemic / physiology*
  • Humans
  • K562 Cells
  • Leukemia, B-Cell / genetics
  • Leukemia, B-Cell / metabolism
  • Leukemia, B-Cell / pathology
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Mice
  • Mice, Inbred C3H
  • Mice, Transgenic
  • Phosphorylation / physiology
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / genetics*
  • Transcription Factor AP-1 / metabolism*
  • U937 Cells


  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • TCL1A protein, human
  • Tcl1 protein, mouse
  • Transcription Factor AP-1
  • PTPRO protein, human
  • Ptpro protein, mouse
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3