A worldwide consortium that comprises biomedical researchers co-led by Alexander Bick, MD, PhD, at the Vanderbilt University Medical Centre, has come up with a new way to gauge the precancerous clones of blood stem cells that would go on to help the doctors lower the blood cancer risk among patients.
This technique, which is referred to as PACER, led to the gene identification that, when activated, goes on to drive clonal expansion. The findings that happened to be published in Nature suggested that the drug that targets this gene, TCL1A, may very well suppress clonal growth as well as associated cancers.
Bick, along with Siddhartha Jaiswal, MD and PhD, from Stanford University and the study’s co-corresponding author, opines that they think TCL1A is a new significant drug target so as to prevent blood cancer. Apparently, more than 10% of the older adults go on to develop somatic mutations, which are the non-inherited mutations in the blood cells that can push explosive clonal expansion when it comes to abnormal cells, thereby increasing the risk of blood cancer and cardiovascular disease.
Bick has over the years contributed to more than 30 scientific papers that have revealed the mysteries of clonal growth. With age, dividing cells within the body acquire mutations, and most of them happen to be innocuous passenger mutations. But at times, a mutation occurs that apparently drives the clone’s development, thereby causing cancer.
Prior to the study, the scientists could only evaluate clonal growth through comparing blood samples that were taken decades apart. Bick, apart from his other colleagues figured out a path that would determine the growth rate for a single timepoint by counting the passenger mutations.
Bick compares these mutations to the rings on a tree: the more rings the tree has, the older it gets. He adds that if one knows how big it is, they can very well estimate the growth rate.
This PACER technique, when it comes to determining the clonal expansion rate because of passenger approximation, was applied to over 5000 individuals who went on to acquire specific, cancer-associated driver mutations across their blood stream known as clonal hematopoiesis of indeterminate potential, also known as CHIP, but they did not suffer from blood cancer.
Through making use of genome-wide association study, researchers also went on to look for genetic variations that had been associated with varied clonal growth rates. To their surprise, it was discovered that TCL1A, a type of gene that had not impacted the blood stem biology before, happened to be a major driver in terms of clonal expansion once it was activated.
The scientists also inferred that a commonly inherited variant when it comes to the TCL1A promoter—the DNA regions that, in due course, initiate transcription and thereby the activation of the gene—was associated with the slower clonal pace of expansion and a significantly reduced prevalence of numerous driver mutations across CHIP, which happens to be the second stage of blood cancer development.
It is well to note that the experimental studies also demonstrated that the variant does suppress the activation of the gene.
As per Bick, some people happen to have a mutation that secures TCL1A from getting turned on, thereby protecting them from rapid clone growth as well as blood cancer. This is what makes this gene more interesting in terms of a potential drug target. He went on to add that this research is going ahead with the hope of gauging more significant pathways that are relevant when it comes to precancerous growth in other tissues and also in the blood.
