Research has identified a rare genetic variant that slows the growth of mutated blood stem cells, thereby reducing the risk of leukemia. This discovery provides insights into natural resistance to clonal expansion and age-related blood cancers, even in individuals with acquired mutations.
Background on Clonal Hematopoiesis
As human tissues age, they accumulate mutations that can contribute to cancer development. In the hematopoietic system, these mutations often manifest as clonal hematopoiesis (CH), where specific blood stem cell (HSC) clones gain a growth advantage and expand over time. This condition, also known as CHIP (clonal hematopoiesis of indeterminate potential), is linked to an elevated risk of blood cancers and other chronic conditions, including heart disease. However, not all individuals with CHIP develop disease, and some mutant stem cell clones show stability or even decline, suggesting the presence of inherited or environmental factors that can inhibit or slow CH progression.
Research Findings
A meta-analysis of genome-wide association studies (GWAS) involving over 640,000 individuals was conducted by Gaurav Agarwal and colleagues to identify inherited DNA variants that offer protection against CH. The study identified a noncoding regulatory variant, rs17834140-T, which significantly lowers the risk of CHIP and decreases the probability of developing blood cancers.
Mechanism of Action
The protective effect of rs17834140-T is attributed to a single DNA change that diminishes the activity of the musashi RNA binding protein 2 (MSI2) gene, a crucial element in stem cell maintenance. Through experiments using gene-edited human HSCs, researchers found that rs17834140-T disrupts a binding site for the endothelial transcription factor GATA-2. This disruption leads to reduced MSI2 expression in HSCs, which subsequently suppresses a network of genes that mutant stem cells require for competitive growth. The same gene network was observed to be highly active in HSCs carrying high-risk cancer mutations and in children with acute myeloid leukemia, correlating with reduced survival rates in these cases.
Clinical Implications
Francisco Caiado and Markus Manz noted in a related Perspective that the study supports MSI2 targeting as a potential therapeutic strategy applicable across various cancers, with small-molecule approaches currently in preclinical development.
Research Integrity and Data Sharing
Regarding research integrity, author Vijay G. Sankaran highlighted that improvements in human genetics and genomics have occurred through routine data sharing, particularly the public release of sequencing datasets and GWAS summary statistics. Sankaran indicated that this study benefited from such data ecosystems and expressed a desire for broader requirements for timely data deposition to facilitate equitable reuse.