Connecting genetics with epigenetics in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive, difficult-to-treat cancer. Nonetheless, researchers have found that there are not as many genetic mutations associated with AML as with most other cancers. Aberrant epigenetic patterning, on the other hand, is emerging as a hallmark of AML.

Epigenetics refers to chemical compounds on DNA or proteins that do not change the DNA sequence but help regulate gene expression. While genetic mutations can lead directly to dysfunction, epigenetic changes affect when and how much genes are expressed. Aberrant changes can undermine the intricate system of checks and balances that govern cellular growth and function, with too much and/or too little of certain genes being expressed. The result can be dysfunction and disease, including cancer.

It is known that epigenetic regulator genes are among the relatively few genes that are frequently mutated in AML. In addition, epigenetic heterogeneity is a hallmark of AML, meaning that different cancerous cells within the same patient can have different epigenetic signatures. But do the genetic mutations result in epigenetic diversity within the same patient? In “Somatic mutations drive specific, but reversible epigenetic heterogeneity states in AML,” published in Cancer Discovery, a team led by Jackson Laboratory (JAX) Assistant Professor  Sheng Li, Ph.D.Applies data integration and machine learning to advance the frontiers of cancer epigenomics and evolution. Sheng Li, Ph.D., and Professor Ari M. Melnick, M.D., of Weill Cornell Medicine, establish, for the first time, that there can indeed be a connection between the genetic mutations and the striking epigenetic diversity in AML. Their findings also indicate that epigenetic diversity in some leukemias may arise as a byproduct of AML disease progression following transformation, and that the two scenarios are not mutually exclusive.

Among the mutations that do affect epigenetic heterogeneity and transformation, the research team found that a mutation to a gene known as isocitrate dehydrogenase (IDH) in particular led to increased epigenetic diversity prior to malignant transformation and development of AML in mice. They speculate that the various epigenetic states may lead to a subset of cells that silence 45 genes that are normally expressed in hematopoietic (blood cell-developing) cells, eventually facilitating leukemogenesis. The study also shows that epigenetic heterogeneity in AML patients is of clinical importance, with increased diversity indicating a corresponding increase in disease severity. It may be that the epigenetic diversity enables subsets of AML cells to survive exposure to therapies.

The researchers show that epigenetic therapies are able to partially reverse the cellular complexity in mice, however. Combining epigenetic therapies with standard therapies may therefore provide an intriguing AML therapeutic option by reducing the chance that cell subsets evade treatment and thereby improving therapeutic response.