Abstract
BackgroundAberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown.MethodsWe screened genome-wide for aberrant CpG island methylation in three disease stages of a murine AML model that is driven by hypomorphic expression of the hematopoietic transcription factor PU.1. DNA methylation levels of selected genes were correlated with methylation levels of CD34+ cells and lineage negative, CD127-, c-Kit+, Sca-1+ cells; common myeloid progenitors; granulocyte-macrophage progenitors; and megakaryocyte-erythroid progenitors.ResultsWe identified 1,184 hypermethylated array probes covering 762 associated genes in the preleukemic stage. During disease progression, the number of hypermethylated genes increased to 5,465 in the late leukemic disease stage. Using publicly available data, we found a significant enrichment of PU.1 binding sites in the preleukemic hypermethylated genes, suggesting that shortage of PU.1 makes PU.1 binding sites in the DNA accessible for aberrant methylation. Many known AML associated genes such as RUNX1 and HIC1 were found among the preleukemic hypermethylated genes. Nine novel hypermethylated genes, FZD5, FZD8, PRDM16, ROBO3, CXCL14, BCOR, ITPKA, HES6 and TAL1, the latter four being potential PU.1 targets, were confirmed to be hypermethylated in human normal karyotype AML patients, underscoring the relevance of the mouse model for human AML.ConclusionsOur study identified early aberrantly methylated genes as potential contributors to onset and progression of AML.
Highlights
Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML)
Disease progression is associated with alterations in global DNA methylation In order to determine DNA methylation changes in the progression of leukemic cells, we used the murine AML model driven by hypomorphic expression of the hematopoietic transcription factor PU.1 and Methyl-CpG immunoprecipitation (MCIp) as a screening tool
Targets of aberrant DNA methylation in the PU.1 mouse model are relevant for the pathogenesis of human myeloid malignancies To identify genes potentially involved in the onset of AML, we looked for overlaps between the list of 1,229 genes or other genomic locations indicated by aberrantly methylated probes in the preleukemic stage (Additional file 3) and gene lists from previously published genomewide DNA methylation data derived from the HELP (HpaII tiny fragment enrichment by ligation-mediated PCR) assay in human myelodysplastic syndrome (MDS) and AML [17]
Summary
Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy associated with severe morbidity and poor prognosis. It comprises a highly heterogeneous group of blastic myeloid malignancies and constitutes the most frequent type of acute leukemia in adults [1]. AML can arise de novo and secondarily from preceding myelodysplastic syndrome (MDS), or after cytotoxic treatment or radiotherapy. It is characterized by an aggressive clonal proliferation of immature hematopoietic progenitor cells (myeloblasts) and impaired differentiation [2]. Many reports have proposed that additional pathogenetic mechanisms, such as aberrant loss or gain of gene function due to epigenetic dysregulation, are of similar relevance for AML pathogenesis [5,6,7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
