UChicago scientists decode key mutation in many cancers

Inside every cell, inside every nucleus, your continued existence depends on an incredibly complicated dance. Proteins are constantly wrapping and unwrapping DNA, and even minor missteps can lead to cancer.

A new study from the University of Chicago reveals a previously unknown part of this dance—one with significant implications for human health.

In the study, published Oct. 2 in Nature, a team of scientists led by UChicago Prof. Chuan He, in collaboration with University of Texas Health Science Center at San Antonio Prof. Mingjiang Xu, found that RNA plays a significant role in how DNA is packaged and stored in your cells, via a gene known as TET2. This pathway also appears to explain a long-standing puzzle about why so many cancers and other disorders involve TET2-related mutations—and suggests a set of new targets for treatments.

“This represents a conceptual breakthrough,” said He, who is the John T. Wilson Distinguished Service Professor in the Department of Chemistry and the Department of Biochemistry and Molecular Biology and an investigator of the Howard Hughes Medical Institute.

“Not only does it offer targets for therapy for several diseases, but we are adding to the grand picture of chromatin regulation in biology,” he said. “We hope the real-world impact is going to be very high.”

RNA revelations

He’s lab has made several discoveries that shook up our picture of how genes are expressed. In 2011, they found that, in addition to modifications to DNA and proteins, modifications to RNA may also control what genes are expressed.

Since then, He and his team have found more and more ways that RNA methylation is fundamentally involved in which genes are turned on and off in both the plant and animal kingdoms.

With this lens, they turned their attention to a gene called TET2. For a long time, we’ve known that when TET2 or TET2-related genes are mutated, all sorts of problems follow. These mutations occur in 10-60% of different human leukemia cases, and pop up in other types of cancers as well. The problem was that we didn’t know why—which significantly hampers the search for treatments.

The other members of the TET family act on DNA, so for years, researchers had been looking at TET2’s effects on DNA. But He’s lab found they’d been looking in the wrong place: TET2 actually affects RNA.

When your cells print their own copies of your genetic material, they have to be neatly packaged up and folded for later reference; the packages are known as chromatin. If that doesn’t happen correctly, all sorts of issues can follow. It turns out that RNA is a key player in this process, and that its role is controlled by TET2 through a modification process called methylation.

Through a clever set of experiments, removing genes and seeing what happened, the He lab team showed how this works. They found that TET2 controls how often a type of modification known as m⁵C occurs on certain types of RNA, which attracts a protein known as MBD6, which in turn controls the packaging of chromatin.

When you’re an infant and your cells are actively dividing into different types of cells, TET2 loosens up the reins so that chromatin can be more easily accessed and stem cells can turn into other cells. But once you’re an adult, TET2 is supposed to tighten up the reins. If that repressing force gets lost, MBD6 has free rein, and havoc can ensue.

“If you have a TET2 mutation, you reopen this growth pathway that could eventually lead to cancer—especially in the blood and brain, because this pathway looks to be most important in blood and brain development,” said He.

As a final confirmation, the team tested human leukemia cells in petri dishes. When the team removed the cells’ ability to create MBD6, effectively pulling on the reins, the leukemia cells all died.

‘A silver bullet’

The most exciting part of this discovery to cancer researchers is that it gives them a whole new set of targets for drugs.

“What we hope we can get from this is a silver bullet to selectively get rid of just cancer cells, by targeting this specific pathway activated because of TET2 or IDH loss,” said He, who is working with UChicago’s Polsky Center for Entrepreneurship and Innovation to found a startup company to create just such a drug.

But we also know that TET2 mutations have consequences other than cancer. TET2 mutations also occur in a fraction of all adults older than 70 and contribute to an increased risk of heart disease, stroke, diabetes, and other inflammatory conditions, a condition known as CHIP.

“These patients have TET2 mutant blood cells, but they haven’t yet caused cancer,” explained Caner Saygin, an oncologist and assistant professor of medicine at the University of Chicago Medicine who specializes in treating CHIP patients and is also working with the He lab on several projects. “But these TET2 mutant cells are more inflammatory, and as they circulate, they cause an increased risk for things like heart, liver, and kidney diseases. Right now, I cannot prescribe anything to these patients because they don’t have cancer yet, but if we could eliminate those mutant cells, we could improve their lives.”

A radical change

The finding is also a radical change in our understanding of chromatin—and hence gene expression as a whole.

Previously, we knew that one form of RNA methylation called m⁶A affects gene expression—its placement and removal affects the packaging of chromatin, which directs which stretches of DNA are translated into reality.

But if m⁵C is also in this category, that suggests this is a general mechanism to control chromatin and gene expression, and there could be more. “If there’s a second, you could have a third, fourth, fifth,” said He. “This says that RNA modification on chromatin is a major mechanism for chromatin and gene transcription regulation. We think this pathway is just the tip of the iceberg.”

Citation: “RNA m⁵C oxidation by TET2 regulates chromatin state and leukaemogenesis.” Zou, Dou, and Li et al, Nature, Oct. 2, 2024.

Funding:  National Institute of Health.