Newly identified rare genetic variant reduces leukemia risk

Newly identified rare genetic variant reduces leukemia risk

A newly identified and rare genetic variant slows the growth of mutant blood stem cells, researchers report, and reduces the risk of leukemia. The results shed light on why some people are naturally more resistant to clonal expansion and age-related blood cancers, despite having acquired risky mutations. As tissues age, they quietly accumulate many mutations that can cause cancer. In the hematopoietic or hematopoietic system, such mutations often occur in otherwise healthy individuals as clonal hematopoiesis (CH), a process in which certain blood stem cell (HSC) clones gain a growth advantage over non-mutant clones, allowing them to proliferate steadily over time. This condition, also known as CHIP (clonal hematopoiesis of undetermined potential), is associated with an increased risk of blood cancers and other chronic diseases, including heart disease. However, not all people with CHIP develop disease, and some mutant stem cell clones remain stable or even decline over time, suggesting that inherited and/or environmental factors may inhibit or slow CHIP.

To investigate this, Gaurav Agarwal and colleagues conducted a GWAS meta-analysis using data from more than 640,000 people to look for inherited DNA variants that protect against CH. Agarwalet al.identified a noncoding regulatory variant, rs17834140-T, that significantly reduces the risk of CHIP and reduces the likelihood of developing blood cancer. According to the results, this protective effect is due to a single DNA change 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, Agarwalet al.discovered that rs17834140-T disrupts a binding site for the endothelial transcription factor GATA-2. This interference decreasesMSI2expression in HSCs, further repressing an entire network of genes that mutant stem cells rely on for competitive growth. Notably, the authors also found that the same gene network was unusually active in HSCs carrying high-risk cancer mutations and in children with acute myeloid leukemia, where it was associated with reduced survival. “The ability to predict disease risk at the individual level is a long-standing goal of modern medicine,” write Francisco Caiado and Markus Manz in a related Perspective. “The Study of Agarwalet al.supports MSI2 targeting as a potential pan-cancer therapy approach, and small molecule approaches are in preclinical development.”

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