Researchers have identified a rare genetic variant that slows the growth of mutated blood stem cells, leading to a lower risk of developing leukemia. The discovery helps explain why some individuals are naturally more resistant to age-related blood cancers and clonal expansion, even after acquiring risky mutations.
As people age, their tissues collect mutations that can lead to cancer. In the hematopoietic system, these changes often show up as clonal hematopoiesis (CH), where certain blood stem cell clones gain a growth advantage and expand over time. This process is also known as CHIP (clonal hematopoiesis of indeterminate potential) and is linked to higher risks of blood cancers and other chronic diseases like heart disease. However, not everyone with CHIP goes on to develop these illnesses; in some cases, mutant stem cell clones remain stable or shrink, indicating that inherited or environmental factors may slow down CH.
To better understand this phenomenon, Gaurav Agarwal and his team conducted a genome-wide association study (GWAS) meta-analysis using data from over 640,000 people. They discovered a noncoding regulatory variant called rs17834140-T that significantly reduces the risk of CHIP and lowers the chances of developing blood cancers. The protective effect is tied to a single DNA change that decreases activity in the musashi RNA binding protein 2 (MSI2) gene—a key player in maintaining stem cells.
Using gene-edited human hematopoietic stem cells (HSCs), the researchers found that rs17834140-T disrupts a binding site for the endothelial transcription factor GATA-2. This disruption leads to lower MSI2 expression in HSCs and suppresses an entire network of genes needed by mutant stem cells for competitive growth. The same gene network was found to be especially active in HSCs with high-risk cancer mutations and in children with acute myeloid leukemia—where its activity was linked to poorer survival rates.
"The ability to predict disease risk at the individual level is a long-standing goal of modern medicine," wrote Francisco Caiado and Markus Manz in a related Perspective. "The study of Agarwal et al. supports MSI2 targeting as a potential pan-cancer therapeutic approach, and small-molecule approaches are in preclinical development."
