Researchers find an inherited genetic variant that is key in slowing the expansion of blood cell clones

Siddhartha Jaiswal, MD, PhD

About 10 percent of generally healthy people over 70 years of age have a mysterious condition in which mutant stem cell clones begin to take over their blood and immune cell production. This condition is called CHIP (short for clonal hematopoiesis of indeterminate potential) and studies have shown that people with CHIP are more at risk of developing a broad range of serious health problems, such as blood cancers. The dominating clones carry a wide variety of mutations, many of which are in genes that are not typically thought of as cancer genes, such as genes involved in epigenetic regulation of DNA.  Despite knowing about these genes for over 10 years, researchers have struggled to find explanations for why they are so frequently mutated. Now researchers at the Stanford School of Medicine have discovered a key change in the mutant cells that drives this expansion, a discovery that opens a potential pathway for treating CHIP and blood cancers.

”We found that a common factor in these dominant clones is that they turned on a gene called TCL1A, but some people have inherited a version of this gene that impedes clonal expansion,” said assistant professor of pathology Siddhartha Jaiswal, MD, PhD. Jaiswal is co-senior author on the paper discussing the result, which is published in the journal Nature. Former University of Michigan graduate student Joshua Weinstock, PhD, who is now a postdoctoral fellow, and Jayakrishnan Gopakumar, who is an MD PhD student at Stanford, are first authors on the paper. Jaiswal and Alexander Bick, MD, PhD, from Vanderbilt University, led the study, which involved researchers and data from over 75 other institutions.

At the start of life, the approximately 100,000 blood stem cells (called hematopoietic stem cells or HSCs) we carry are very similar. But over time, as they reproduce themselves, these stem cells accumulate various mutations. Some of these mutations, Jaiswal explains, give certain blood stem cells a competitive advantage over others, and they begin to dominate the bone marrow niches where such stem cells live. “In people with CHIP, we see that anywhere from 4% to 100% of their HSCs are clones derived from a single mutated stem cell,” Jaiswal said. 

These clones continue to produce blood and immune cells normally, and there are no obvious signs which betray that someone has CHIP.  “One wouldn’t necessarily assume that if a large proportion of someone’s blood and immune system is derived from a single clone, it would have negative health effects, and yet there is now a large body of evidence that it does,” Jaiswal said. “People with CHIP may seem to be completely healthy, but studies show that they are at higher risk of developing blood cancers, cardiovascular disease, liver disease, chronic obstructive pulmonary disorder and many other disorders.” 

The common denominator for many of these diseases seems to be chronic inflammation, Jaiswal said. “Many of the mutations we observe in the HSCs also have effects on the immune cells that derive from them,” he said. “These mutations may cause innate immune cells to be more inflammatory.” In another paper published in the same issue of Nature, researchers, including Weinstock, Bick and Jaiswal, showed how CHIP increases the risk of chronic liver disease and cirrhosis due to excessive inflammation caused by mutated macrophages infiltrating the liver.

In order to understand why these mysterious genes are so frequently mutated in HSCs, Jaiswal and his colleagues developed a new technique that allowed them to infer the speed at which a clone was expanding based on a single sample. The researchers called this technology PACER, and they applied it to samples from 5,071 people with CHIP. Once they knew the clonal expansion rate of a clone, they could perform analyses to identify inherited changes in the genome that were associated with clonal expansion, which could implicate specific genes important for the fitness of the mutant cells.

“What we found was that there were a number of cases of CHIP where a common inherited variant , in TCL1A was associated with slower expansion of HSCs,” Jaiswal said. So even if someone was unlucky enough to gather mutations in genes that might lead to clonal expansion, having a certain inherited variant of the TCL1A gene had a protective effect, he said. About one third of those with European heredity, and two thirds of those with African heredity, have one or two copies of the protective version of the gene, he said.   

Additional work by the researchers showed that TCL1A was normally “off” in HSCs, but some CHIP mutations resulted in TCL1A getting turned “on”, which caused the clones to expand. In those carrying the protective variant of the TCL1A gene, the gene did not get turned “on” as effectively, which the researchers think explains why these people had clones that grew more slowly.

The discoveries carry hope that drugs could be developed to limit clonal expansion in CHIP and even cases of leukemia or other disease. Prior to our study, it was not exactly clear how you would clinically target the genes that drove clonal expansion, but now we can hope that by targeting TCL1A, we might be able to slow clonal expansion and treat these disorders.”

The work described in the paper was supported by the Ludwig Center for Cancer Stem Cell Research, the NHLBI’s TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I), and TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I), the Burroughs Wellcome Foundation, the American Society of Hematology, an NIH Director's New Innovator Award (DP2-HL157540), and the Leukemia and

Lymphoma Society.

Technology described in the paper has been licensed to the company TenSixteen Bio, in which Jaiswal and Bick have a stake.