Fig. 7: Activation of the STING pathway by ERVs promotes increased self-renewal and skewed lineage populations in DNMT3A-mutated HSCs.

The mutated DNMT3A in HSCs leads to genome-wide hypomethylation. Beyond impacting gene regulation, this also results in the upregulation of previously silenced ERVs due to the absence of cytosine methylation-associated transcriptional inhibition. The increased ERV RNA can be reverse-transcribed into cDNA, which in turn activates the STING pathway and induces chronic inflammation in DNMT3A-mutated HSCs. This STING-dependent autonomous inflammation leads to increased self-renewal and biased lineage differentiation in DNMT3A-mutated HSCs. Inhibition of STING mitigates these phenotypes and prevents the development of leukemia associated with DNMT3A mutations in mouse models.