Background: Involvement of mutations in epigenetic mechanism in the development of
heterogeneous MDS and its evolution to AML has been understood with at least one mutation and
median of 2-3 mutations of the landscapes of driver mutations in ~40 genes described in >90% MDS
patients. Exclusivity and cooperating effects of mutations have directed therapeutic implementation
with hypomethylating agents and identified a number of first-in-class small molecules as inhibitors
of mutational expression. Preclinical and clinical trials have already been initiated for some synthetic
and natural products and established proof-of-concept for mitigation of mutagenic effects.
Objective: The present review article entails the mutational signatures in DNA-methylation and hydroxymethylation,
histone acetylation and Deacetylation, polycomb repressor complex (PRC2), and
small molecule inhibitors of these mutational expressions.
Method: Information has been collected from the recently published literature available mainly
through Google search in Medline and PubMed database. Special emphasis was paid on the literature
available during 2009-2016.
Result: The up-to-date information accumulated on signature-mutations and their inhibitors has to
integrate the function of clonal hematopoiesis of indeterminate potential (CHIP) and mutational
complexities for re-defining MDS-genesis. Nevertheless, molecular understanding of MDS heterogeneity
and its transformation to AML is expanding at fast pace with expanding knowledge on
abundant non-coding RNAs (ncRNAs), which forms the basis of targeted drug-tailoring, and will
further develop personalized medicines based on individual genetic blue-prints.
Conclusion: Mutation-specific targeted epigenetic drugs, which have already sensitized drug-makers
and regulators, may promise attestation of ‘del5q and lenalidomide’-like specific drugs for every
mutational signature independently or in combination with standard therapeutic elements used for
MDS-management, and that will add to understand their antagonistic/synergistic effects.