Hierarchical Epigenetic Modifications and Clonal Evolution

 Perturbations of epigenetic gene regulation are emerging as a hallmark of acute myeloid leukemia (AML).   Studies profiling cytosine methylation in de novo AML patients reveal specific patterns of aberrant DNA methylation patterning suggesting that this disease can be classified into distinct subtypes.   Aberrant gene specific cytosine methylation has been shown in various cases to contribute leukemia phenotypes.  In many cases epigenetic signatures have been instructive in the identification of novel leukemia driving mechanisms.  Notably, only some of these cytosine methylation signatures are linked to specific genetic lesions.  Moreover de novo AML cases display a core leukemic cytosine methylation signature independent of AML subtype and genetic lesions.  Hence genetics and epigenetics are not always linked. The epigenome exhibits considerable plasticity, which is crucial to its purpose in enabling cells to naturally undergo phenotypic changes in response to environmental cues and during differentiation.    This same characteristic could conceivably endow the epigenome with greater susceptibility to variation between individual cells populating tissues such as bone marrow.  Epigenetic variability could potentially increase in malignant tissue due to sustained proliferation or other mechanisms. Genetic heterogeneity and clonal evolution in AML is implicated in various aspects of disease pathogenesis and phenotype.    It is not known to what extent epigenetic heterogeneity might occur in AML, and if so, whether it might have functional consequences, whether it might be linked to specific genetic lesions, or be associated with somatic mutation burden.   Several approaches have been developed to quantify epigenetic heterogeneity at least in the cytosine methylation compartment.  Some of these methods are able to discriminate discrete epigenetic alleles.  It is possible that epigenetic allele burden could emerge as a feature that is linked to more aggressive disease.  Epigenetic allele evolution patterning may also be indicative of clonal composition of AML although it may or may not associate with its genetic clonal evolution counterpart.    Another important question is whether specific genomic elements are more prone to epigenetic variability, are functionally relevant and could contribute to leukemia heterogeneity.    Emerging studies are describing for the first time the nature of epigenetic allele diversity, evolution and variability in AML and other hematologic malignancies.    These new discoveries and their potential clinical implications will be discussed.