Editors' ChoiceAcute Myeloid Leukemia

HELP Is On the Way!

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Science Translational Medicine  17 Feb 2010:
Vol. 2, Issue 19, pp. ec24
DOI: 10.1126/scitranslmed.3000957

The role of genetic changes in myeloid malignancies such as acute myeloid leukemia (AML) or myelodysplasia (MDS), which often precedes AML, is well appreciated. However, recent work demonstrates the importance of epigenetic changes that affect gene expression, including DNA methylation, in myeloid and other malignancies. Indeed, DNA methyltransferase inhibitors are approved for the treatment of MDS. For de novo AML not arising from preexisting MDS, less is known about the importance of DNA methylation. Now, Figueroa et al. apply a method, which they previously used in MDS samples, to comprehensively measure DNA methylation changes and their relationship to genetic changes and clinical outcome in de novo AML patient samples.

Their method, HpaII tiny fragment enrichment by ligation-mediated PCR (HELP), restricts DNA with methylation-specific restriction enzymes followed by hybridization to genome-wide promoter microarrays in order to determine global DNA methylation changes. HELP divided AML patients into 16 distinct categories, effectively subdividing the previous genetic categories. HELP also identified a 15-gene DNA methylation classifier that independently predicted overall survival in test and validation cohorts of AML patients, even after controlling for all known covariates.

Given these results and the previous information on activity of DNA methyltransferase inhibitors in MDS, it is logical to study the biological significance of these methylated genes in leukemia formation and to prospectively test DNA methyltransferase inhibitors in AML patients with adverse DNA methylation changes. HELP illustrates the power of discovery platforms to globally assess epigenetic changes in cancer, which may then be targeted rationally with epigenetic therapies.

M. E. Figueroa et al., DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 17, 13–27 (2010). [Full Text]

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