How Do Genetic Mutations Drive or Protect from Deadly Diseases?

University of Miami Miller School of Medicine researchers are studying STAT3 mutations that lead to lymphomas and leukemias.

There’s a double agent at work.

Most of the time, a protein transcription factor known as STAT3 (Signal Transducer and Activator of Transcription 3) is all about protection, staving off infections and inflammatory diseases. But STAT3 mutations can cause too much or too little immune system activation, leading to lymphomas and leukemias.

Researchers at the University of Miami Miller School of Medicine are taking a deeper dive into STAT3, examining 75 genetic mutations associated with lymphomas and leukemias, with the hope of accelerating targeted, precise treatments for blood cancers.

“We’re trying to understand how changes in structure, which we are able to predict, manifest in changes to function, which we’re able to measure,” said Alejandro Villarino, Ph.D., associate member of the Sylvester Comprehensive Cancer Center and assistant professor in the Department of Microbiology and Immunology at the Miller School.

The Nature of STAT3 Mutation

STAT3 and related factors orchestrate T-cell responses that “are more good than bad,” Dr. Villarino said. “They do all types of essential things for us when get an infection to coordinate our immune responses.”

Genetic mutations in STAT3, however, may cause overactive or underactive responses, and the outcome for patients doesn’t vary. They get cancer.

“We’re finding examples of mutations that go in both directions, but the patients manifest in essentially the same types of lymphomas,” Dr. Villarino said. “In some cases, STAT3 seems to be working less and causing cancer. And in some cases, it seems to be working more and causing cancer.”

Cancer-related changes to STAT3 are somatic genetic mutations, which form early on from hematopoietic stems cells. These cells differentiate into white blood cells that fight infections. But, as they mature, they replicate many times, increasing the opportunity for mutations.

Miller School researchers are studying mutations in STAT3 which may account for up to 5% of hematopoietic or blood cell cancers.

That may not sound like a lot, “but that is one in 20 people,” said Aaron Benedict Schultz, MS, project researcher and the first graduate student to join Dr. Villarino’s laboratory.

STAT3 also plays a role in other malignancies, including some solid tumors, so potential implications are broad.

From Critical Care to STAT3 Mutations

Protein transcription factors and genetic mutations were not always Schultz’s calling.

“I worked for eight years as a critical care paramedic,” he said. ”A lot of the people we helped were in the later stages of cancer or in later stages of a medical condition, who couldn’t be transported from point A to B safely on their own.”

Schultz’s experience in critical care persuaded him to join the Miller School for his Ph.D. work, and choosing Miami was easy for him “because of how much UM cares about advancing care for patients and how much the Miller School of Medicine invests into the students who are really on the front lines of research.”

Schultz also credits Dr. Villarino for providing guidance and passion for the work.

“I really feel like he is giving me the ability to become the best researcher that I can be,” said Schultz, “so that later on down the road, we can get rid of some of these diseases.”

Tags: Dr. Alejandro Villarino, Sylvester Comprehensive Cancer Center