Retroviral Integration Mutagenesis in Mice and Comparative Analysis in Human AML Identify Reduced PTP4A3 Expression as a Prognostic Indicator

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 potentially have a role in AML, on one hand as a candidate HIG contributing to leukemogenesis in mice and on the other hand as a prognostic indicator in human AML.

LEO1 Is Regulated by PRL-3 and Mediates Its Oncogenic Properties in Acute Myelogenous Leukemia

“…In recent years, accumulating evidence suggests that PRL-3 is also a novel therapeutic target and biomarker in leukemia (13,14). We were the first to report that elevated PRL-3 protein expression occurs in about 47% of human acute myelogenous leukemia (AML) cases while absent from normal myeloid cells in bone marrow (13).…”

“…We were the first to report that elevated PRL-3 protein expression occurs in about 47% of human acute myelogenous leukemia (AML) cases while absent from normal myeloid cells in bone marrow (13). In addition, a large-scale gene expression profiling study of 454 primary AML samples demonstrates that high PRL-3 levels is an independent negative prognostic factor in AML, both for overall survival and event-free survival (14). These reports collectively suggest that PRL-3 may be of biologic and clinical relevance in AML and warrants further investigation.…”

Phosphatase of regenerating liver in hematopoietic stem cells and hematological malignancies

“…52,53 High PRL3 mRNA expression is associated with FLT3-ITD mutations and poor prognosis in AML patients with normal karyotype. 52,53,85 Internal tandem duplication of FMS-like tyrosine kinase (FLT3-ITD) is well known to be involved in acute myeloid leukemia (AML) progression, but FLT3-ITD-negative AML cases account for 70% to 80% of AML, and the mechanisms underlying their pathology remain unclear. [48][49][50][51] PRL3 is upregulated in 40% of FLT3-ITD-negative AML patients.…”

“…In addition, PRL3 expression level correlates with poor survival of the AML patients, and the AML relapses accompany with re-upregulation of PRL3, 86 suggesting that PRL3 is important for the proliferation and survival of both FLT3-ITD-positive and FLT3-ITD-negative AML cells. 52,53,85,86 Chronic myeloid leukemia (CML) is caused by the t(9;22) chromosomal translocation that results in the expression of the fusion tyrosine kinase BCR-ABL. Tyrosine kinase inhibitor (TKI) therapy has led to long-term remissions, but patients remain BCR-ABLC.…”

“…[11][12][13][14] Given that PRLs are upregulated in some hematological malignancies and important for the proliferation, survival and migration of malignant cells through enhancing oncogenic signaling pathways, 52,53,[84][85][86]92,100 PRLs may be potential therapeutic targets in hematological malignancies.…”