Activation of the TP53 pathway is a therapeutic vulnerability in NUP98::KDM5A+ pediatric AML III

Using matched fetal and adult hematopoietic stem and progenitor cell models, we demonstrate that NUP98::KDM5A-driven leukemia originating in a fetal context exhibits enhanced 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 activation. Pharmacologic inhibition of TRIP13 or combined treatment with idasanutlin, navitoclax, and 5-azacytidine—three clinically approved agents—effectively reactivates TP53 signaling and induces synergistic apoptosis in NUP98::KDM5A AML models. These findings reveal a developmentally regulated TRIP13/PPM1D–TP53 survival axis exploitable for targeted therapy, offering a mechanistically grounded and translatable strategy to improve outcomes for this high-risk pediatric leukemia.