The activation of TP53 pathway is a therapeutic vulnerability in NUP98::KDM5A+ pediatric acute megakaryoblastic leukemia

Abstract

NUP98::KDM5A fusion drives 15% of pediatric acute megakaryoblastic leukemia, an aggressive subtype with poor prognosis and no targeted therapies. Matched fetal and adult hematopoietic stem and progenitor cell models revealed that fetal NUP98::KDM5A-driven leukemia shows superior aggressiveness and sustains fetal-specific transcriptional programs. Functional genomic and proteomic analyses identified a critical dependency on the AAA+ ATPase TRIP13, which binds the phosphatase PPM1D to suppress TP53. Pharmacologic inhibition of TRIP13 or combined treatment with idasanutlin, navitoclax, and 5-azacytidine effectively reactivated TP53 signaling and induced synergistic apoptosis across NUP98::KDM5A-positive models. These findings reveal a developmentally regulated TRIP13/PPM1D–TP53 survival axis that can be exploited for targeted therapy, offering a mechanistically grounded and translatable strategy to improve outcomes for this high-risk pediatric leukemia patients.