New Study Highlights Role of TET Proteins in Blood Cancers

Some proteins drive the cellular overgrowth that leads to cancer, while others act as cancer suppressors. TET1 and TET2 do both. Research led by scientists at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine has uncovered the role these proteins play in cancer development, potentially leading to new treatments.

TET proteins are enzymes with a highly specific role — demethylating DNA. This is important because DNA methylation shuts down gene activity; it frees genes to express themselves, produce RNA and ultimately proteins. Gene expression can be good or bad, depending on the gene and the situation.

The TET family of proteins was discovered only a few years ago and, ever since, scientists have been trying to figure out what they do under different conditions. For example, in normal cells, TET2 is a tumor suppressor.

“TET2 acts as a brake on overgrowth,” said Mingjiang Xu, M.D., Ph.D., researcher at Sylvester and associate professor of biochemistry and molecular biology at the Miller School of Medicine. “If you lose TET2, blood stem cells can self-renew and proliferate faster. It’s one of the most common mutations in blood cancers.”

In November 2015, Xu and colleagues published a paper in the prestigious journal Cell Reports about the different roles TETs 1 and 2 play in cancer development in animal models, uncovering a complicated path.

The research team focused on two forms of blood cancer — myeloid, which starts in bone marrow, and lymphoid, which originates in the lymphatic system. TET proteins play important roles in both cancer types, but in completely different ways. For example, losing TET2 can lead to myeloid cancer. However, animals that also lost TET1 were spared.

“Now we know that having TET1 is essential for TET2 loss to initiate myeloid cancer,” said Xu. “Losing both can prevent myeloid cancer.”

That is good news, but it’s a double-edged sword. While protected from myeloid cancer, animals that lost both TET proteins were at much greater risk for lymphoid cancer.

TET1 and TET2 have overlapping responsibilities, demethylating some of the same genes and allowing them to express accordingly. But each protein has its own individual responsibilities, demethylating separate genes, which is why the relationship can be so complicated.

Now that scientists have a much better understanding of these two proteins, they can leverage that information to develop more targeted cancer treatments.

“A TET1 inhibitor could be used to treat myeloid cancer,” said Xu. “At present, we really have no effective treatment.”

Scientists face a complex relationship. Suppressing TET1 could fight myeloid but, as noted above, suppressing both proteins could cause lymphoid cancer. In addition, if doctors increase levels of TET1, but leave TET2 alone, they could have a cancer-preventing effect for lymphoid cancer.

In other words, to take advantage of the TET family’s relationship with cancer, researchers must develop finely tuned agents that precisely target TET1 — to either increase or decrease it, depending on the cancer — without affecting TET2.

“These findings are promising, but we need to hit the right target,” said Xu. “It will probably require some form of nanotechnology to guide the inhibitor exactly where we want it. It needs to be TET1-specific.”

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