Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma

Targeting DNA2 is synthetically lethal in myeloma cells that undergo metabolic adaptation and rely on oxidative phosphorylation to maintain survival after DNA damage activation. Overall design: To discover novel mechanisms through which MM cells overcome DNA damage, we investigated how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting ILF2, a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo an adaptive metabolic rewiring and rely on oxidative phosphorylation to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identified the DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2-ASO?induced DNA damage, as being essential to counteracting oxidative DNA damage and maintaining mitochondrial respiration.