Abstract
Close to half of de novo acute myeloid leukemia (AML) cases do not exhibit any cytogenetic aberrations. In this regard, distortion of the DNA methylation setting and the presence of mutations in epigenetic modifier genes can also be molecular drivers of the disease. In recent years, somatic missense mutations of the DNA methyltransferase 3A (DNMT3A) have been reported in ~20% of AML patients; however, no obvious critical downstream gene has been identified that could explain the role of DNMT3A in the natural history of AML. Herein, using whole-genome bisulfite sequencing and DNA methylation microarrays, we have identified a key gene undergoing promoter hypomethylation-associated transcriptional reactivation in DNMT3 mutant patients, the leukemogenic HOX cofactor MEIS1. Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.
Highlights
Acute myeloid leukemia (AML) comprises a group of hematopoietic malignancies derived from myeloid precursors that have a highly heterogeneous clinical course and response to therapy
To find downstream hypomethylated targets mediated by the DNA methyltransferase 3A (DNMT3A) mutational event, we have taken an unbiased epigenetic approach to examine the entire DNA methylome at the singlenucleotide level of a well known DNMT3A AML mutant cell line (OCI-AML3, which harbors a heterozygous R882C mutation)[10] and a widely used DNMT3A wild-type AML cell line (AML5)
The complete wholegenome bisulfite sequencing data from OCI-AML3 and AML5 are illustrated in Figure 1a, and are available for download from NCBI GEO (National Center for Biotechnology Information Gene Expression Omnibus): http://www.ncbi.nlm.nih.gov/geo/query/ acc.cgi?token=crcvqguqdhwxrsf&acc=GSE62303
Summary
Acute myeloid leukemia (AML) comprises a group of hematopoietic malignancies derived from myeloid precursors that have a highly heterogeneous clinical course and response to therapy. We observed that DNMT3A mutant AML cells had a 9% (66.1% vs 75.1%) decrease in average DNA methylation level and fewer methylated CpG dinucleotides than did the DNMT3A wild-type cells (Figures 1b and c).
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