The receptor-type protein tyrosine phosphatase, PTPRO, is known to induce cell contact inhibition, cell cyclearrest, terminal cell differentiation and apoptosis in human cancer cell lines, particularly leukemia cells. Ourstudy has shown that PTPRO is suppressed by hypermethylation in human primary tumors (hepatocellular,lung and CLL) as well as leukemia and lung cancer lines, and that ectopic expression of the full length formPTPRO-FL in non-expressing cells inhibited anchorage-independent growth, delayed re-entry of the cells intocell cycle, increased susceptibility to apoptosis and inhibited tumor growth in nude mice. Further, PTPRO islocalized to chromosome 12p12.3 that is characterized by loss of heterozygosity in a variety of human cancer,a characteristic of many tumor suppressor genes. In addition, patients exhibiting PTPRO promotermethylation had higher expression of at least three anti-apoptotic proteins (Bcl2, Mcl-1, XIAP) independent ofother commonly known prognostic factors including interphase cytogenetics, VH and p53 mutational status.The hypothesis of this project is that PTPRO has the potential for functioning as a growth/tumor suppressorthat could be utilized as a novel molecular target in cancer, particularly CLL, therapy.
The specific aims are to( 1) Investigate whether PTPROt (predominant form in cells of lymphoid origin) expression is down-regulatedin chronic lymphocytic leukemia (CLL), whether PTPRO promoter methylation identifies a subset of high riskgroup of CLL patients, and whether the suppression of PTPROt correlates inversely with the methylationstatus/density of the CpG island located in the promoter (2) confirm the growth/tumor suppressor property oranti-transformation potential and pro-apoptotic property of PTPROt isoforms, (3) identify the substrate(s) ofthe PTPROt isoforms and (4) elucidate the molecular mechanism by which methylation suppressedexpression of PTPRO by (a) exploring the chromatin structure of PTPRO promoter (b) investigating whetherthe novel post-translational modifications of core histones (identified in Project 4) are associated with thePTPRO promoter in normal B lymphocytes and whether this association is altered in CLL(c) determining theinvolvement of DNA methyltransferases, methyl CpG binding proteins, and chromatin remodelers (studied inProject 5) in regulating PTPRO expression in CLL cells. Project 1 will interact with this project in studies onre-activation of the suppressed genes by agents that inhibit DNA methyltransferases and histonedeacetylases. It is hoped that this study will provide a novel molecular target in CLL therapy and molecularmarker for CLL, and could reveal the potential for drug resistance in a subset of CLL patients with PTPROmethylation independent of other commonly known prognostic markers.
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