Taken together, our work uncovers a novel synthetic lethality through combinatory therapy of co-targeting PI3K/AKT and WNT/β-catenin pathways as a valuable druggable targets for PRL-3 high AML and provides strong rationale to further develop these strategies to treat this subtype of AML patients with high PRL-3 who are associated with poor prognosis in clinic. Here, PTP4A3 is linked to acute myeloid leukemia.