Vogler, M. | bioRxiv Science

bioRxiv2025

The activation of TP53 pathway is a therapeutic vulnerability in NUP98::KDM5A+ pediatric AML

NUP98::KDM5A-rearranged pediatric acute myeloid leukemia (AML) is a rare, infancy-predominant entity with dismal outcome and no targeted therapeutic options. Given its suspected fetal origin, we hypothesized that leukemic maintenance depends on developmentally restricted vulnerabilities embedded within fetal hematopoietic programs. Using matched fetal and adult hematopoietic stem and progenitor cell models, we integrated transcriptomic and proteomic profiling with CRISPR-Cas9 screenings to define ontogeny-specific dependencies in NUP98::KDM5A leukemia. Fetal-derived NUP98::KDM5A leukemias exhibited greater in vivo aggressiveness, and retained fetal transcriptional signatures compared with adult counterparts. A comparative CRISPR-Cas9 screen using a library targeting fetal gene programs, conducted in both fetal- and adult-derived NUP98::KDM5A leukemias, identified the AAA ATPase TRIP13 as a selective and essential dependency in the fetal context. Mechanistically, TRIP13 physically interacted with the TP53 phosphatase PPM1D/WIP1, resulting in suppression of TP53 activation. Genetic ablation of Trip13, or pharmacologic inhibition using DCZ0415, a small-molecule inhibitor targeting TRIP13, reactivated TP53, induced G2/M arrest and mitochondrial apoptosis, and depleted leukemic cells in vitro; these effects were fully rescued by TP53 loss. In competitive transplantation assays, Trip13 ablation significantly impaired leukemic fitness in vivo. Together, these findings define a developmentally restricted TRIP13-PPM1D-TP53 survival axis in NUP98::KDM5A AML and provide mechanistic proof-of-concept that reactivation of the TP53 signaling pathway via TRIP13 inhibition represents a therapeutically targetable vulnerability in this high-risk pediatric leukemia. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/675580v4_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@143d103org.highwire.dtl.DTLVardef@14f3225org.highwire.dtl.DTLVardef@655541org.highwire.dtl.DTLVardef@c021ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Computational modeling of DLBCL predicts response to BH3-mimetics.

In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. Variability in the expression and sequestration of these proteins in Diffuse Large B cell Lymphoma (DLBCL) likely contributes to variability in response to BH3-mimetics. Successful deployment of BH3-mimetics in DLBCL requires reliable predictions of which lymphoma cells will respond. Here we show that a computational systems biology approach enables accurate prediction of the sensitivity of DLBCL cells to BH3-mimetics. We found that fractional killing of DLBCL, can be explained by cell-to-cell variability in the molecular abundances of signaling proteins. Importantly, by combining protein interaction data with a knowledge of genetic lesions in DLBCL cells, our in silico models accurately predict in vitro response to BH3-mimetics. Furthermore, through virtual DLBCL cells we predict synergistic combinations of BH3-mimetics, which we then experimentally validated. These results show that computational systems biology models of apoptotic signaling, when constrained by experimental data, can facilitate the rational assignment of efficacious targeted inhibitors in B cell malignancies, paving the way for development of more personalized approaches to treatment.

systems biology↗