CO53 | Targeting the PA2G4-NPM1 axis triggers nucleolar stress in NPM1c acute myeloid leukemia

Introduction: NPM1 mutation, the most common genetic alteration in acute myeloid leukemia (AML), remains a therapeutic limitation. Although preclinical strategies targeting NPM1 showed promise, clinical translation has been limited. Developing compounds that selectively target NPM1-mutated (NPM1c) AML cells, especially in high-risk molecular contexts, endures as a major translational challenge.Methods: We identified PA2G4 interactors in AML cells by PA2G4 pulldown followed by nLC-MS/MS and validated PA2G4-NPM1 interaction by co-immunoprecipitation (co-IP). We functionalized a PA2G4 inhibitor, WS6, with a biotin tag on the terminal piperazine ring for anti-biotin co-IP studies. We assessed WS6 effects in NPM1c models using in vitro functional assays, analyzed transcriptomic changes by RNA sequencing, and tested in vivo efficacy in an NPM1c patient-derived xenograft (PDX) model.Results: Our group previously demonstrated that the RNA-binding protein PA2G4 functions as a bystander of Myc signaling in 3q26 AML. Given the role of Myc in high-risk AML, we subsequently extended our investigation of PA2G4 to broader AML subtypes. From the mass spectrometry (MS) analysis of PA2G4 interactors (n=167, P