retroviral integration mutagenesis in mice and comparative analysis in human aml identify reduced ptp4a3 expression as a prognostic indicator逆转录病毒整合诱变在小鼠和人类aml比较分析确定减少ptp4a3表达式作为一个预后指标.pdfVIP

Retroviral Integration Mutagenesis in Mice and Comparative Analysis in Human AML Identify Reduced PTP4A3 Expression as a Prognostic Indicator ´ 1 1 1 1 1,2 Renee Beekman , Marijke Valkhof , Stefan J. Erkeland , Erdogan Taskesen , Veronika Rockova , 1 1 ¨ 1 1 Justine K. Peeters , Peter J. M. Valk , Bob Lowenberg , Ivo P. Touw * 1 Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands, 2 Department of Biostatistics, Erasmus University Medical Center, Rotterdam, The Netherlands Abstract Acute myeloid leukemia (AML) results from multiple genetic and epigenetic aberrations, many of which remain unidentified. Frequent loss of large chromosomal regions marks haplo-insufficiency as one of the major mechanisms contributing to leukemogenesis. However, which haplo-insufficient genes (HIGs) are involved in leukemogenesis is largely unknown and powerful experimental strategies aimed at their identification are currently lacking. Here, we present a new approach to discover HIGs, using retroviral integration mutagenesis in mice in which methylated viral integration sites and neighbouring genes were identified. In total we mapped 6 genes which are flanked by methylated viral integration sites (mVIS). Three of these, i.e., Lrmp, Hcls1 and Prkrir, were up regulated and one, i.e., Ptp4a3, was down regulated in the affected tumor. Next, we investigated the role of PTP4A3 in human AML and we show that PTP4A3 expression is a negative prognostic indicator, independent of other prognostic parameters. In conclusion, our novel strategy has identified PTP4A3 to