As blood-forming tissues age, they accumulate mutations that can give some blood stem cells a growth advantage, a process known as clonal hematopoiesis (CH). When this occurs without overt disease, it is called CHIP and is linked to higher risks of blood cancers and other conditions, though many people with CHIP never become ill, implying the existence of protective factors.
A new study identifies a rare inherited genetic variant that slows the expansion of mutated blood stem cells and lowers leukemia risk. By analyzing genetic data from over 640,000 individuals, researchers found a noncoding variant (rs17834140-T) that reduces the likelihood of CHIP and blood cancers.
This protective effect works by weakening activity of the MSI2 gene, which is important for stem cell maintenance. The variant disrupts binding of the transcription factor GATA-2, lowering MSI2 expression and suppressing a gene network that mutant stem cells depend on for competitive growth. The same network is highly active in high-risk stem cells and in acute myeloid leukemia, where it is linked to poor outcomes. Overall, the findings help explain why some individuals are naturally more resistant to clonal expansion and age-related blood cancers, and they highlight MSI2 as a potential therapeutic target.
Credit: GEN News