MYC-induced hypertranscription is a driver of pathological vascular remodeling in sporadic arteriovenous malformations

Here, we identify hypertranscription as a defining feature of endothelial cells (ECs) in sporadic arteriovenous malformations (AVMs), which are caused primarily by somatic activating KRAS mutations in ECs. We demonstrate that expression of mutant KRAS in ECs results in MEK-dependent elevations in rRNA synthesis, ribosome biogenesis, and global transcription and translation.

Mechanistically, our data reveal that MYC lies downstream of KRAS/MEK and that MYC inhibition is sufficient to dampen hypertranscription, migration and cell growth and to rescue vascular enlargement and arteriovenous shunts in a zebrafish model of KRAS-dependent AVMs. Our findings uncover a previously unrecognized KRAS–MEK–MYC–hypertranscription axis driving pathological vascular remodeling in AVMs, revealing that hypertranscription contributes to nonmalignant pathology and offering a potential therapeutic target.