New Target for Blood Cancer Prevention Identified

An international consortium of biomedical researchers led by Alexander Bick, MD, Ph.D., of Vanderbilt University Medical Center has developed a new method for measuring the growth rate of precancerous clones of blood stem cells, which could one day help clinicians with blood cancer prevention in patients. The PACER approach led to the discovery of a gene that, when activated, stimulates clonal proliferation. The findings, which were published in the journal Nature, imply that medications targeting this gene, TCL1A, may be able to limit clonal proliferation and tumors connected with it.

“We think that TCL1A is a new important drug target for preventing blood cancer,” said Bick, the study’s co-corresponding author with Stanford University’s Siddhartha Jaiswal, MD, Ph.D.

More than 10% of elderly people get somatic (non-inherited) mutations in blood stem cells, which can result in explosive, clonal expansions of defective cells, raising the risk of blood cancer and cardiovascular disease.

Bick, who joined VUMC in 2020 as an assistant professor of Medicine in the Division of Genetic Medicine and the head of the Vanderbilt Genomics and Therapeutics Clinic, has contributed to more than 30 research studies that are shedding light on the secrets of clonal proliferation (hematopoiesis).

Mutations occur in the body’s dividing cells as they age. The majority of these mutations are harmless “passenger” mutations. However, occasionally a mutation occurs, causing the creation of a clone and, eventually, cancer.

Prior to this study, scientists would compare blood samples taken decades apart to determine clonal growth rate. By counting the number of passenger mutations, Bick and his colleagues were able to calculate the growth rate from a single time point.

“You can think of passenger mutations like rings on a tree,” Bick said. “The more rings a tree has, the older it is. If we know how old the clone is (how long ago it was born) and how big it is (what percentage of blood it takes up), we can estimate the growth rate.”

The PACER technique was used to calculate the “passenger-approximated clonal expansion rate” in over 5,000 people who had specific, cancer-associated driver mutations in their blood stem cells, known as “clonal hematopoiesis of indeterminate potential” or CHIP, but did not have blood cancer.

The researchers then used a genome-wide association study to seek genetic variants associated with distinct clonal growth rates. They were surprised to discover that TCL1A, a previously unknown gene in blood stem cell biology, was a primary driver of clonal proliferation when activated.

The researchers also discovered that a commonly inherited variant of the TCL1A promoter, the DNA region that normally initiates transcription (and thus gene activation), was associated with a slower rate of clonal expansion and a significantly lower prevalence of several driver mutations in CHIP, the second step in the development of blood cancer.

Experiments revealed that the variation inhibits gene activation.

“Some people have a mutation that prevents TCL1A from being turned on, which protects them from both faster clone growth and from blood cancer,” Bick said. That’s what makes the gene so interesting as a potential drug target for blood cancer prevention.

He stated that the research is still ongoing in the hopes of uncovering more critical pathways pertinent to precancerous growth in other tissues as well as blood.

The study included researchers from more than 50 institutions in the United States, as well as Germany, Sweden, and the Netherlands. Taralyn Mack, Benjamin Shoemaker, MD, MSCI, and Dan Roden, MD were also VUMC co-authors.

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