Advancing precision therapy in pediatric acute myeloid leukemia through PDX models and mitochondrial targeting.

In pediatric acute myeloid leukemia (pAML) relapse/refractory (R/R) disease occurs frequently, but underlying mechanisms are unclear and effective second-line therapeutic options remain limited. Although genomic characterization has advanced targeted treatments, their clinical implementation, particularly in the pediatric field, is hindered by toxicities or resistance due to poor correlation between preclinical and clinical studies. The use of more robust preclinical models is crucial for developing effective therapies. We established 26 patient-derived xenografts (PDXs) of pAML representing 14 high-risk genetic subtypes. These PDXs faithfully recapitulated the molecular complexity and heterogeneity of primary AML, and preserved the immunophenotypic, genomic, and transcriptomic profiles. Clonal and transcriptomic dynamics were tracked from patient samples to their matched PDXs, and vulnerabilities that could be exploited as therapeutic targets were identified, facilitating the evaluation of multifaceted therapeutic strategies. We selected druggable variants and aberrantly activated pathways in KMT2A-rearranged (KMT2A-r) AML and performed an in vitro drug screening of actionable targets exploiting a predictive 3-dimensional coculture model. Promising compounds were tested in vivo in AML PDXs. Among new drugs targeting variants and pathways, we demonstrate that the combination of IACS-010759, a mitochondrial complex I inhibitor, and venetoclax, a B-cell lymphoma 2 inhibitor, reduces AML progression in KMT2A-r PDXs modeling both disease onset and relapse. The combination of venetoclax with IACS-010759 with a stromal targeting drug slowed AML progression in a resistant model. Overall, our study highlights the power of AML PDXs as a translational platform for novel targeted therapy identification. Our preclinical results testing venetoclax with IACS-010759 in KMT2A-r AML strongly support mitochondrial targeting in this genetic AML subtype.