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Review
. 2016 Feb:36:100-6.
doi: 10.1016/j.gde.2016.03.011. Epub 2016 May 7.

Genetic and epigenetic heterogeneity in acute myeloid leukemia

Sheng Li  1 , Christopher E Mason  2 , Ari Melnick  3
Affiliations
Review

Genetic and epigenetic heterogeneity in acute myeloid leukemia

Sheng Li et al. Curr Opin Genet Dev. 2016 Feb.

Abstract

Genetic and epigenetic heterogeneity is emerging as a fundamental property of human cancers. Reflecting the genesis of tumors as an evolutionary process driven by clonal selection. The complexity of clonal architecture has been known for many years in the setting of acute myeloid leukemia (AML), based on karyotyping studies. However the true complexity of AMLs is only now being understood thanks to in depth genome sequencing studies in humans, which reveal that heterogeneity is a multilayered and involves not only the genome but also the epigenome. Here, we review recent advances in genetic and epigenetic heterogeneity and clonal dynamics in AML and their relevance to biology, clinical outcomes and therapeutic implications. Special attention is focused on somatic mutations affecting regulators of cytosine methylation, since these tend to occur early in disease evolution, reprogram the epigenome of hematopoietic stem cells, and are linked to unfavorable outcome.

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Figures

Figure 1
Figure 1. Genetic and epigenetic evolution of AML
The illustration depicts the sequential acquisition of somatic mutations, with founding mutations enriched in epigenetic regulators, and late mutations enriched in proliferative activated signaling. Epigenetic states are altered accordingly impacted by the sequential acquisitions of somatic mutations. The epigenetic heterogeneity and epiallele shift evolves over time. Epigenetic heterogeneity refers to global variability in the methylation state of cytosine residues. Epiallele shift represents focal epigenetic allelic diversity.
Figure 2
Figure 2. Proposed epigenetic and genetic models with different leukemia cell fitness and clinical outcome
Model 1 is AML with low genetic and epigenetic heterogeneity. Perhaps these cases would display the most favorable clinical outcomes. Model 2 is AML with high genetic and but low epigenetic heterogeneity, with intermediate clinical outcome. Model 3 is AML with high genetic and but low epigenetic heterogeneity, also with putative intermediate clinical outcome. Model 4 is AML with high genetic and epigenetic heterogeneity, with possible unfavorable clinical outcome.
See this image and copyright information in PMC

References

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