Increased 1-carbon cycle turnover in AML results in elevated production of genotoxic formaldehyde. AML upregulates POLQ to repair formaldehyde-DNA-protein cross-links (DPCs). Deficiency of POLQ DNA repair in AML results in accumulation of DPCs and resultant cytotoxicity. Inhibition of POLQ presents an opportunity to harness endogenous formaldehyde as a novel therapeutic strategy against AML. Professional illustration by Patrick Lane, ScEYEnce Studios.