Effect of methionine restriction on gene expression of non-KMT2A-rearranged NALM-6 and KMT2A-rearranged SEM BCP-ALL cell lines

Current intensive chemotherapy regimens have improved overall survival in pediatric acute lymphoblastic leukemia but fail to cure some high-risk patient subgroups. While exploring amino acid depletion strategies, we observed that KMT2A-rearranged (KMT2A-r) leukemia, an aggressive subset with a dismal prognosis, is particularly vulnerable to perturbations of the methionine cycle. We demonstrated that this methionine dependency is primarily driven by an increased need for S-adenosylmethionine 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, successfully impaired leukemia progression in patient-derived xenograft models, and a high-throughput drug screen revealed a strong synergy between MAT2A inhibition and histone deacetylase inhibitors. Our results identified the methionine cycle as a targetable vulnerability in KMT2A-r leukemia, which may increase the efficacy of epigenetic targeting agents.