Rare Inherited Genetic Variant Protects Against Blood Cancer, Reduces Leukemia Risk

As tissues age, they quietly accumulate many mutations that can drive cancer. In the hematopoietic system, such mutations often appear in otherwise healthy individuals as clonal hematopoiesis (CH), a process in which certain blood stem cell (HSC) clones gain a growth advantage over non-mutated clones, allowing them to expand steadily over time.

A condition known as CHIP (clonal hematopoiesis of indeterminate potential) is associated with an increased risk of blood cancers as well as other chronic illnesses, including heart disease. However, not all those with CHIP develop disease, and some mutant stem cell clones remain stable or even diminish over time, suggesting that inherited and/or environmental factors can restrain or slow CH.

Now, a newly identified and rare genetic variant has been identified that slows the growth of mutated blood stem cells and reduces the risk of leukemia. The findings offer insight into why some people are naturally more resistant to clonal expansion and age-related blood cancers despite acquiring risky mutations.

This work is published in Science in the paper, “Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.”

To gain further insight into this process, the lab of Vijay G. Sankaran, MD, PhD, at Harvard Medical School performed a GWAS meta-analysis on data from more than 640,000 individuals to search for inherited DNA variants that protect against CH. The team identified a noncoding regulatory variant, rs17834140-T, that substantially lowers the risk of CHIP and reduces the likelihood of developing blood cancers.

“The ability to predict disease risk at the individual level is a long-standing goal of modern medicine,” write Francisco Caiado, PhD, and Markus Manz, MD, both from the department of medical oncology and hematology at the University Hospital Zurich, Switzerland, in the related Perspective entitled, “Genetic resistance to leukemia.” “The study of Agarwal et al. supports MSI2 targeting as a potential pan-cancer therapeutic approach, and small-molecule approaches are in preclinical development.

According to the findings, this protective effect traces to a single mutation that weakens the activity of the musashi RNA binding protein 2 (MSI2) gene—a key factor in stem cell maintenance. Using gene-edited human HSCs, the team discovered that rs17834140-T disrupts a binding site for the endothelial transcription factor GATA-2. This interference reduces MSI2 expression in HSCs, which further suppresses an entire network of genes that mutant stem cells rely on for competitive growth. Notably, the authors also found that this same gene network is unusually active in HSCs carrying high-risk cancer mutations and in children with acute myeloid leukemia, where it was associated with reduced survival.