Identification of differentially methylated markers among cytogenetic risk groups of acute myeloid leukemia

Abstract

Abbreviations: AML, acute myeloid leukemia; CHARM, comprehensive high-throughput array-based relative methylation analysis; DMR, differentially methylated region; TCGA, The Cancer Genome Atlas Research NetworkAberrant DNA methylation is known to occur in cancer, including hematological malignancies such as acute myeloid leukemia (AML). However, less is known about whether specific methylation profiles characterize specific subcategories of AML. We examined this issue by using comprehensive high-throughput array-based relative methylation analysis (CHARM) to compare methylation profiles among patients in different AML cytogenetic risk groups. We found distinct profiles in each group, with the high-risk group showing overall increased methylation compared with low-and midrisk groups. The differentially methylated regions (DMRs) distinguishing cytogenetic risk groups of AML were enriched in the CpG island shores. Specific risk-group associated DMRs were located near genes previously known to play a role in AML or other malignancies, such as MN1, UHRF1, HOXB3, and HOXB4, as well as TRIM71, the function of which in cancer is not well characterized. These findings were verified by quantitative bisulfite pyrosequencing and by comparison with results available at the TCGA cancer genome browser. To explore the potential biological significance of the observed methylation changes, we correlated our findings with gene expression data available through the TCGA database. The results showed that decreased methylation at HOXB3 and HOXB4 was associated with increased gene expression of both HOXB genes specific to the mid-risk AML, while increased DNA methylation at DCC distinctive to the high-risk AML was associated with increased gene expression. Our results suggest that the differential impact of cytogenetic changes on AML prognosis may, in part, be mediated by changes in methylation.

DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T‐Cell Acute Lymphoblastic Leukemia

“…Genetic subtypes of childhood ALL and AML have been associated with DNA methylation signatures . A recent study by Amabile et al.…”

“…Genetic subtypes of childhood ALL and AML have been associated with DNA methylation signatures. [24][25][26] A recent study by Amabile et al showed that in a murine chronic myeloid leukemia (CML) model, induction of BCR-ABL could trigger DNA methylation changes. Furthermore, it was shown that aberrant DNA methylation had the potential to contribute to leukemia progression in primary CML cells.…”

Hox Genes in Adult Tissues and Their Role in Endothelial Cell Differentiation and Angiogenesis

“…Other groups demonstrated that HoxA13 was associated with the development of monocytes and macrophages, and its expression was observed more often in monocytic leukemia cell lines in comparison with other types of leukemia [40]. Moreover, the expression of genes HOXB3 and HOXB4 has been found to be altered in patients with AML with poor prognosis [41].…”

Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

“…Considering the fact that UHRF1 is overexpressed in various solid [5, 24] and haematological tumors [25, 26] and that UHRF1 via its domains (Fig. 1) guarantees a strong relationship between DNA methylation and histone post-translational changes [5, 6, 27, 28], targeting this epigenetic actor could be a new promising anticancer strategy.…”