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

Pediatric acute myeloid leukemia (AML) driven by the NUP98::KDM5A fusion is an aggressive subtype predominantly arising in infancy, with limited therapeutic options and poor prognosis. In thsi study we used 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 reactivated TP53 signaling and induced synergistic apoptosis in a synergistic manner in NUP98::KDM5A AML 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 patient.

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Cifarelli, L.N., Activation of the TP53 pathway is a therapeutic vulnerability in NUP98::KDM5A+ pediatric AML. bioRxiv. 2025; doi: https://doi.org/10.1101/2025.09.11.675580