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6.07.2017

Discovering AML’s Epigenetic Identity

Maria Figueroa, M.D., a researcher at Sylvester Comprehensive Cancer Center and associate professor of human genetics at the University of Miami Miller School of Medicine, published a paper in the journal Cancer Discovery that provides new insights into how certain molecular pathways influence acute myeloid leukemia (AML).

Working closely with Ari Melnick, M.D., professor of medicine at Weill Cornell Medicine, and others, Figueroa helped identify epigenetic mechanisms that delineate several AML subtypes and could lead to new treatment options.

“We could use the epigenetic profile to see that some patients are different,” said Figueroa. “They belong together, and they behave clinically as a subset.”

The key is the cancer’s epigenome. Over the past 20 years, researchers have learned that it is not just the genes we have that matters, but how those genes are expressed. Epigenetic modifications are little molecular switches that can turn genes on and off. In cancer, quite often, those switches go awry.

Focusing on methylation
Figueroa’s paper focused on an epigenetic mechanism called methylation, which generally turns genes off. The team was leveraging better sequencing technology to revisit work they had done in 2010. But now, rather than assessing thousands of sites in the genome, they have the ability to look at millions.

The researchers were surprised to find that these methylation changes weren’t always taking place on genes. Quite often, they were affecting so-called “junk DNA,” which is far more important than scientists previously thought.

“We started learning that DNA methylation is not all about promoters [DNA sequences that turn genes on],” said Figueroa. “Epigenetically, junk DNA is very active, there’s a lot of regulation. And it is precisely methylation at these regions that most accurately distinguishes patients with different AML subtypes.”

The study confirmed the significance of two proteins that commonly are found to have mutated in AML — DNMT3A and IDH. DNMT3A adds the methyl switch that turns off genes. Though not technically an epigenetic gene, when mutated, IDH affects other genes that remove those same switches.

How patients differ
These findings can separate patients by their IDH/DNMT3A mutation status. They might have both mutations, just one, or neither of them. These potential combinations matter, since the double IDH/DNMT3A mutation may expose a chink in AML’s armor. The combination seems to turn on a cancer driver called RAS/MEK, making these leukemia cells more sensitive to inhibition of this pathway. Dr. Figueroa and colleagues believe MEK inhibitors might help this distinct group of AML patients.

“If you have these two mutations, you would be predicted to be more sensitive to inhibition of the RAS/MEK signaling pathway,” said Figueroa. “It would give the rationale for a clinical trial.”

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