Scientists have begun unraveling the molecular intricacies that drive the appetite of acute myeloid leukemia for fat. They found that these tumor cells have particularly low levels of PHD3, an enzyme that normally activates ACC2 to repress fatty-acid oxidation. This fuels the cells' metabolic reliance on fat-burning, but also renders them highly susceptible to inhibitors of fatty-acid oxidation.

Scientists from Harvard Medical School in Boston, MA, have begun unraveling the molecular intricacies that drive the appetite of acute myeloid leukemia (AML) for fat. Their study implicates PHD3, a member of an enzyme family best known for regulating glycolytic metabolism through HIF1α in an oxygen-dependent manner.

“We were interested in identifying other targets for these enzymes besides HIF1α,” says senior author Marcia Haigis, PhD, “and the interaction between PHD3 and ACC [a key regulator of fatty-acid homeostasis] was by far the most dominant signature we found, using an unbiased proteomic approach.” Her team showed that in response to nutrient abundance, PHD3 hydroxylates a proline residue on one of ACC's two isoforms, ACC2, which is then activated to repress fatty-acid oxidation in cells.

This discovery is in line with “the well-accepted idea, nowadays, that the PHD family responds to multiple metabolic inputs, not just oxygen,” Haigis notes. As for ACC2, it has thus far been better understood in the opposite context of active fat-burning: A different enzyme, AMPK, responds to low nutrient availability by phosphorylating and inactivating ACC2; this in turn boosts fatty-acid oxidation to help restore cellular energy levels. “Our data suggest that, together, AMPK and PHD3 toggle fatty-acid oxidation in a manner sensitive to both high and low nutrient status,” Haigis says.

Next, the researchers combed through Oncomine, a cancer microarray database, and discovered that PHD3 expression was particularly low in AML. They made a similar observation when clustering AML patient samples from The Cancer Genome Atlas according to high or low PHD3 expression—nearly 80% fell in the latter category. When the team treated PHD3-low AML cell lines with the angina medicine ranolazine (Ranexa; Gilead) or the purely experimental agent etomoxir, both of which inhibit fatty-acid oxidation, they found that the cells were exceedingly sensitive to either one.

“These tumor cells are so addicted to fat, they didn't just stop growing when we suppressed fatty-acid oxidation; they died shortly afterwards,” Haigis says. “We couldn't rescue them with sugar. It looks like blocking fat-burning is strongly cytotoxic in AML.” Her team also inhibited fatty-acid oxidation by more than 50%—a level similar to that achieved with etomoxir—through another route: They reexpressed high levels of PHD3 in AML cells; in a mouse model of the disease, this improved survival.

Grahame Hardie, PhD, of the University of Dundee in Scotland, UK, observes that “the number of additional targets identified for the PHD family remains in single figures, so this discovery that PHD3 hydroxylates and activates ACC2 is very exciting.” Low PHD3 expression may be useful in predicting sensitivity to inhibitors of fatty-acid oxidation, he says. That PHD3 is a nutrient sensor which essentially antagonizes the effects of AMPK—the latter was first identified by Hardie and his group in 1987—is also intriguing, and “confirming this idea remains an important challenge for the future.”

Haigis agrees, noting that more basic research is needed before these findings can be extrapolated to the clinic. “Metabolic reprogramming in cancer is incompletely understood because most of the focus has been on glucose,” she says. “Many tumors are FDG [fluorodeoxyglucose]–PET-negative, though, and we're just beginning to scratch the surface of understanding why. How they handle fat could provide a more complete picture; ours is just an early chapter in the story.” –Alissa Poh