DNMT/G9a Complex Inhibition Uncovers Epigenetic Vulnerabilities and Induces IFN-Response in Acute Myeloid Leukemia

Epigenetic dysregulation is a hallmark of Acute Myeloid Leukemia (AML), with mutations in DNA Methyltransferases (e.g., DNMT3A) being frequent and promising therapeutic targets. DNMTs form complexes with Histone Methyltransferases (HMTs), driving gene silencing loop via chromatin methylation crosstalk. However, potential connections between this DNMTs/HMTs cooperative activity and oncogenic requirements across the AML mutational spectrum remain poorly understood. Here, we demonstrate that AMLs carrying DNMT3A and Nucleophosmin (NPM1) mutations exhibit a specific epigenetic vulnerability toward a complex formed by DNMTs and G9a, a specific histone H3 Lysine 9 Methyltransferase (H3K9-HMT). Dual inhibition of DNMT/G9a restores differentiation, reduces tumor growth, and spares healthy progenitors compared to standard hypomethylating agents. Mechanistically, DNMT/G9a regulates NPM1 stability, inhibits HOXA9/MEIS1 activity, and triggers interferons (IFN) response via viral mimicry pathways by modulating hypermethylated retrotransposons. Collectively, our data unravel specific epigenetic vulnerabilities within the complex AML mutational landscape and provide a compelling rationale for the design of personalized epigenetic therapies with enhanced efficacy and safer clinical outcomes.