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Aberrant Methylation in Hematological Malignancies

Venu K. Thirukonda, Radha Raghupathy and Samir Parekh

Epigenetics encompasses heritable changes in gene expression without alterations in genetic sequence. Among the multiple epigenetic regulators of gene expression, methylation of cytosine in genomic DNA is amongst the most stable and best studied. Expanding knowledge of aberrant methylation in hematological malignancies has increased its applicability in diagnosis, classification, prognostication and prediction of treatment response. Genome-wide methylation profiling can differentiate between clinically relevant subtypes of non-hodgkin’s lymphoma (NHL) as well as distinguish monoclonal gammopathy of unknown significance (MGUS) from multiple myeloma (MM). New subcategories of normal karyotype acute myeloid leukemia (AML) with distinct canonical pathways and different disease behavior have also been identified by methylation studies. Methylation scores can predict outcomes in chronic lymphocytic leukemia (CLL). Genes with tumor suppressor function are frequently silenced by methylation and may be amenable to therapeutic intervention. DNA hypomethylating agents azacitidine and decitabine have been approved by the FDA for treatment of myelodysplastic syndrome (MDS). Clinical trials of newer agents including histone deacetylase inhibitors (HDAC-i) are showing great promise in different hematological malignancies. High-resolution methylation analysis using massively parallel sequencing (MPS) is likely to further improve our understanding of disease pathogenesis and identify novel therapeutic approaches in hematological malignancies. In this review article we will describe recent advances in methylation studies and the current and potential future impact of this knowledge on management of hematological malignancies.