Many patients with acute myeloid leukemia (AML) share a mutation in a gene called IDH. A University of Colorado Cancer Center study published this week in the journal Leukemia & Lymphoma shows that this IDH mutation may be the first domino in a chain that leads to a more aggressive form of the disease.
"In fact, it's not IDH itself that causes the problem," says Dan Pollyea, MD, MS, investigator at the CU Cancer Center and assistant professor of hematologic oncology at the University of Colorado School of Medicine. Rather, the mutation in IDH leads to exponentially higher blood levels of a protein called 2-hydroxyglutarate. This protein "mucks up," as Pollyea says, other genes that in turn promote cancer or fail to inhibit its growth.
The recent study shows that AML patients in remission who retain high levels of 2-hydroxyglutarate due universally to IDH mutation are much more likely to relapse than patients without similarly elevated levels.
The chain of causation includes another couple links.
"2-hydroxyglutarate reduces genes' ability to regulate themselves," says Pollyea. Over time genes accumulate gunk in the form of methylation these methyl groups attach to silence parts of gene promoters, helping to decide which genes are and are not turned into proteins. Too much methylation is associated with many cancers, including AML. And 2-hydroxyglutarate turns off one of the body's methylation-regulating genes.
So an IDH mutation leads to high 2-hydroxyglutarate, leads to bad gene regulation, leads to hypermethylation, leads to AML.
Pollyea hopes to stop the first domino from falling by targeting IDH mutations. "Imagine screening for patients prospectively and then if they have the mutation, we could use something like an IDH inhibitor," Pollyea says. Turn off this mutation and doctors may be able to turn of the disease, or at least its most aggressive characteristics.
But the genetic te
|Contact: Garth Sundem|
University of Colorado Denver