Abstract 276: Role of AP1 elements and TCL1 protein in regulation of the gene encoding PTPROt (protein tyrosine phosphatase receptor-type O) in chronic lymphocytic leukemia

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The gene for protein tyrosine phosphatase receptor-type O encodes two functional isoforms in a tissue-specific manner. The full-length form is expressed in epithelial cells, particularly in the brain and kidney, whereas the truncated form (PTPROt) is primarily expressed in hematopoietic cells. We have previously demonstrated that PTPROt is a bona fide tumor suppressor (J Biol Chem. 2009 Jan 2;284(1):455-64) and is down-regulated in primary CLL samples (Clin Cancer Res. 2007 Jun 1;13(11):3174-81). Further, studies from two laboratories including ours have shown that Syk and Lyn, two key protein tyrosine kinases involved in B-cell receptor signaling, are substrates of PTPROt, igniting interest in understanding deregulation of this tyrosine phosphatase in CLL. While the PTPRO promoter is methylated, the mechanism of its silencing in the pathogenesis of CLL is unexplored. Here, we utilized the Tcl1 transgenic (Tg) mouse model of CLL and a cell line with TPA-inducible expression of PTPROt to elucidate the mechanism of PTPROt silencing. This study demonstrates that PTPROt is transcriptionally silenced in CD19+ spleen B cells from Tcl1 transgenic (Tg) mouse when compared to wild type mice. As observed with primary human CLL, the methylation of PTPRO CGI (CpG island) is significantly higher in Tcl1 Tg CLL B-lymphocytes than in normal B lymphocytes. Significant suppression of PTPROt is also observed at very early time-point (∼7 wks) in CD19+ spleen B-cells from Tcl1 Tg mice compared to normal spleen B-lymphocytes from age-matched WT mice in the absence of detectable methylation at CGI. This data suggests that transcriptional silencing occurs prior to methylation. To understand further the potential transcriptional mechanism of PTPROt suppression in CLL, the role of AP1 in the expression of this gene was explored. We first demonstrate that AP-1 activation by TPA in U937 cells induces PTPROt expression with concurrent recruitment of c-fos and c-jun to its promoter. PTPROt promoter is also responsive to over- and under-expression of AP-1 confirming the role of AP-1 in PTPROt expression. Next, we demonstrate that Tcl1 can repress PTPROt promoter by altering c-fos expression and c-jun activation state. These findings further substantiate the importance of TCL1 in the pathogenesis of CLL. [Supported, in part, by grants CA101956 and CA086978]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 276. doi:10.1158/1538-7445.AM2011-276