S-adenosylmethionine addiction confers sensitivity to methionine restriction in <i>KMT2A</i>-rearranged acute lymphoblastic leukemia

Current intensive chemotherapy regimens have improved overall survival in pediatric acute lymphoblastic leukemia (ALL) but fail to cure some high-risk patient subgroups. We observed that lysine methyltransferase 2A-rearranged (KMT2A-r) leukemia, an aggressive subset with a dismal prognosis, is particularly vulnerable to perturbations of the methionine cycle. We demonstrate that this methionine dependency is driven by an increased need for S-adenosylmethionine (SAM) to maintain the hypermethylated state of KMT2A-r leukemias. Important pro-survival KMT2A-r target genes are repressed under methionine restriction, which, combined with other downstream metabolic changes, results in rapid cell death. FIDAS-5, an orally active methionine adenosyltransferase 2A (MAT2A) inhibitor that blocks SAM production, successfully impaired leukemia progression in patient-derived xenograft models, and a drug screen revealed strong synergy between MAT2A inhibition and histone deacetylase inhibitors. Our results identify the methionine cycle as a targetable vulnerability in KMT2A-r leukemia, which may increase the efficacy of epigenetic targeting agents.