A recent discovery by a research team from the Massachusetts General Hospital Department of Pathology and the Mass General Cancer Center has the potential to further our big picture understanding of a deadly subtype of leukemia.

Over the past two decades, the growth of personalized medicine has led to a more detailed understanding of the individual genetic drivers of cancer.

Personalized medicine has helped researchers move from a big picture understanding of cancer to a more patient-specific approach. It has led to more specialized screening and treatment strategies that have improved survival rates, reduced side effects, and helped to assess patient risk.

One limitation to this highly specific approach is that strategies which prove successful in treating one genetic subtype of cancer may not extend to other subtypes. Progress often comes in small steps.

However, a recent discovery by a research team from the Massachusetts General Hospital Department of Pathology and the Mass General Cancer Center has the potential to further our big picture understanding of a deadly subtype of leukemia.

The team, led by MGH Research Scholar David Langenau, PhD, identified a little-known protein called TOX that is over-expressed in nearly all types of an aggressive form of leukemia called T cell acute lymphoblastic leukemia (T-ALL).

The discovery could lead to new treatment strategies for T-ALL patients who do not respond to traditional chemotherapy treatments, or those who have relapsed after treatment was initially successful. Treatment-resistant or relapsed T-ALL is highly fatal—approximately 70 percent of children and more than 90 percent of adults eventually die of the disease.

An Achilles Heel

For Dr. Langenau, one of the most exciting aspects of the discovery is that it identifies a common treatment target.

“In T cell leukemias there are more than seven subtypes and each is associated with specific genetic changes,” he explains. “Sadly, this means that T cell leukemias utilize many ways to drive tumor growth and therapies that target specific mutations would be effective in only a small fraction of patients.”

“Rather, what we’ve discovered is sort of an Achilles heel that if we can target it with a drug, we could kill of 95% percent of human T cell leukemias. That’s what makes it so exciting. We’ve now found a universal pathway that these leukemias are addicted to.”

The study, which was published in Cancer Discovery last November, is the result of a project that began seven years ago when Langenau’s team compiled a laundry list of genes that had been linked with T cell leukemia but hadn’t been verified to have roles in cancer growth. The team then put the genes into zebrafish models of T-ALL to see which ones made the leukemias appear more quickly and grow more aggressively.

From that analysis, the team found eight genes of interest. They decided to focus on a little-studied gene called TOX. “At the time, there were less than 10 publications in the world on this gene,” Langenau says. “TOX is the founding member of a class of proteins (TOX 1 through TOX 4), and there is even less known about TOX 2-4.”

As it turns out, the decision paid off.  

The Role of TOX

In laboratory experiments using human leukemia cells, Langenau’s team found that TOX plays a role in cell growth and interacts with the genes that are responsible for finding and replacing breaks in the genome.

Leukemias are caused by mutations which prevent blood cells from maturing properly, which leads to a glut of immature blood cells that prevent normal blood cells from functioning. The mutations are caused by breaks in parts of the genome that drive blood cell behavior. These breaks can occur as a byproduct of normal cell processes, or by exposure to radiation, chemicals or other toxins.

The team found that TOX is expressed at very high levels in leukemia patients, suggesting that it prevents the body from efficiently repairing genetic breaks and ultimately leads to mutational events that cause leukemia. Moreover, TOX is also required for continued growth of leukemia cells through mechanisms not currently known.

“So an average person at some stage in their life has TOX turned on the correct way, but in leukemia, it is off the charts highly overexpressed, and then causes these horrible changes to your genome and eventually leads to cancer,” Langenau says. “Remarkably, high levels of TOX also lock these cells in a state of rapid cell growth.”

Next Steps

The next steps for Langenau’s team will be to focus on TOX as a therapeutic target and to figure out how it is regulating the continued growth of leukemia cells on a molecular level.

“If you make a mouse that completely lacks this protein, they are viable,” says Langenau. “They have some defects, but they are largely normal. And so the idea is that if you can inhibit TOX function with a small molecule drug, it’s not going to affect your normal cells but will have major effects on suppressing leukemia growth. That’s why I am very excited about this work. TOX may be a powerful and nearly universal therapeutic target in this disease.”

The team is also looking to see if TOX plays a role in the progression of other types of cancers.

“We may have identified a brand new class of proteins with a unique function that has not been worked up in any other study to date. It will be exciting to assess whether these TOX proteins have similar roles in other types of tumors.”

About the Mass General Research Scholars

The MGH Research Scholars Program was established to support early career researchers with innovative yet unproven ideas that have the potential to transform the future of medicine. Funded 100% through philanthropy, this program gives researchers the freedom and flexibility they need to follow the science wherever it leads. Time and time again, history has shown that brilliant scientists who are given free rein to explore new frontiers are the ones who make the greatest, often wholly unexpected, advances.

Learn more about the Research Scholars Program.