In conclusion, by mapping DNA methylated viral integration sites in murine leukemias induced by retroviral integration mutagenesis followed by comparative analysis in human AML, we identified PTP4A3 not only as a candidate HIG contributing to leukemogenesis in mice but also as an independent prognostic indicator in human AML. We designed a strategy to identify candidate HIGs in AML using retroviral integration mutagenesis, by mapping DNA methylated proviral integrations. By using HAT, we deliberately aimed at detecting integrations present in the majority of the leukemic cells, which are most likely involved in the early phase of leukemogenesis. At the same time, integrations present in subclones that contribute to later stages of leukemic progression will be missed using this approach. We identified 6 genes that are flanked by methylated viral integrations. Expression analysis showed that Lrmp, Hcls1 and Prkrir ) were up regulated and Ptp4a3, a phosphatase also known as Prl3 was down regulated in the respective murine tumor. These results indicate that a flanking methylated viral integration site does not necessarily lead to transcriptional repression. As 1 out of 4 genes flanked by a mVIS was transcriptionally down regulated and expression of the 2 other genes could not be investigated, the efficiency to detect potential HIGs by identifying mVIS would approximately be 17–25%. However, the number of analysed tumors is too small to allow an accurate estimation of the efficiency. Ptp4a3 expression is controlled by p53 induced after DNA damage in mouse embryonic fibroblasts and its activity is involved in inducing a G1 cell cycle arrest in these cells. Surprisingly however, the same study also demonstrated a cell cycle arrest upon reduction of PTP4A3 expression. Apparently, depending on expression level dosage, PTP4A3 may have both positive and negative effects on cell cycle regulation. Hence, PTP4A3 haplo-insufficiency, but not its complete loss, may lead to an impairment of cell cycle arrest after DNA damage. Dosage effects of PTP4A3 expression in relation to cellular responses may be more complex, particularly in cancer cells. For example, in carcinoma cell lines PTP4A3 expression may lead to down regulation of p53 and it is variably induced by c-irradiation. Finally, high PTP4A3 expression has been linked to increased tumor aggressiveness in different types of solid tumors, e.g., melanoma, gastric cancer, colon cancer, hepatocellular carcinoma and breast cancer, possibly because high PTP4A3 expression leads to increased epithelial-mesenchymal transition. The role of PTP4A3 in hematopoietic malignancies has not been studied as XL-184 extensively as in carcinoma. Only a few studies report differences in expression levels of PTP4A3 in ALL and myeloma subgroups, based on gene expression profiling. Interestingly however, in a recent study, PTP4A3 has been proposed to have a role in drug-resistance in AMLs with internal tandem duplication of FLT3. This finding, together with the observation that high PTP4A3 expression negatively correlates with prognostic outcome, indicates that PTP4A3 might be a potential therapeutic target in AML.