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.
Highlights
Acute myeloid leukemia (AML) is a complex disease driven by multiple cytogenetic abnormalities, such as inv(16), t(8;21), t(15;17), 3q abnormalities, deletions of of chromosome 5 and 7 and by aberrant expression and/or mutations of genes e.g., EVI1, FLT3, RAS, RUNX1, CKIT, WT1, CEBPA and NPM1 [1,2]
methylated DNA immunoprecipitation (MeDIP) was used on a subset of samples to enrich for methylated long terminal repeats (LTRs) and flanking genomic regions
MeDIP enrichment relative to input levels was determined for the LTR, the non-methylated actin B locus (ActB) and the hemimethylated imprinting control region 1 (ICR1) of H19
Summary
Acute myeloid leukemia (AML) is a complex disease driven by multiple cytogenetic abnormalities, such as inv(16), t(8;21), t(15;17), 3q abnormalities, deletions of (the q-arms) of chromosome 5 and 7 and by aberrant expression and/or mutations of genes e.g., EVI1, FLT3, RAS, RUNX1, CKIT, WT1, CEBPA and NPM1 [1,2]. The frequent occurrence of chromosomal deletions suggests that haplo-insufficiencies contribute to the pathogenesis of AML. Because deleted regions often harbor numerous genes, it remains difficult to pin point critical haplo-insufficient genes (HIGs) involved in the pathogenesis of AML. Gene expression profiling (GEP) focusing on down regulated genes could be informative, differences in expression levels may relate to differentiation status of the AML blasts, rather than to mechanisms underlying leukemogenesis [3]. Mapping of minimal affected regions in combination with GEP to identify HIGs often is cumbersome because these regions may still contain numerous genes and differences in their expression level may be subtle. Even in chromosomal regions frequently lost upon leukemic progression, e.g., the q-arm of chromosome 7, identification of critical HIGs remains difficult
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