Abstract SY34-01: Developmental dependency and metabolic vulnerabilities in NUP98-rearranged pediatric leukemia
Authors: Elvin Wagenblast
Journal: Cancer Research (2025)

Abstract Pediatric acute myeloid leukemias (AML) are aggressive malignancies characterized by rapid progression, therapy resistance, and poor outcomes, frequently originating during fetal development or early infancy. Unlike adult leukemias, which generally arise from a decades-long accumulation of genetic mutations, pediatric leukemias emerge following genetic alterations occurring prenatally or shortly after birth. However, the biological mechanisms underlying this age-dependent susceptibility and aggressiveness remain largely unexplained. To address this knowledge gap, we developed a novel humanized model of pediatric AML driven by the NUP98::NSD1 fusion oncogene, clinically associated with chemotherapy resistance and dismal prognosis, particularly when accompanied by mutations in the transcription factor WT1. Using CRISPR/Cas9 genome engineering to induce endogenous expression of this fusion oncogene directly in human primary hematopoietic stem and progenitor cells (HSPCs) isolated from distinct developmental stages, we demonstrate that leukemia initiation, lineage specification, and therapeutic response critically depend on the developmental stage of the initiating cells. We found that fetal-derived HSPCs readily underwent leukemia transformation upon expression of the NUP98::NSD1 fusion, especially when co-occurring with WT1 mutations. In contrast, postnatal HSPCs exhibited progressively diminished leukemia transformation potential. Single-cell RNA-seq and ATAC-seq analyses uncovered distinct transcriptional and epigenetic landscapes associated with developmental stage-specific leukemia initiation, leukemia stem cell hierarchies, and therapeutic vulnerabilities between fetal and postnatal-origin leukemias. Clinically, NUP98-rearranged AML exhibiting fetal-like transcriptional programs correlated strongly with worse patient outcomes. Furthermore, fetal-derived leukemias displayed unique metabolic dependencies, contributing to enhanced therapy resistance. Leveraging these insights, we identified and therapeutically targeted vulnerabilities including oxidative phosphorylation and anti-apoptotic mechanisms. Indeed, therapeutic strategies exploiting these developmental-stage-specific susceptibilities effectively overcame resistance in combination therapies and significantly reduced leukemia burden in our preclinical and patient-derived xenograft models. Together, our findings reveal an unappreciated developmental dimension in leukemia biology, illustrating how developmental context critically shapes leukemia potential, lineage fate decisions, and therapeutic response - even among leukemias with identical oncogenic mutations. This work strongly supports the development of age-specific precision oncology strategies to overcome therapy resistance and improve survival outcomes in pediatric patients with aggressive fusion-driven leukemias. Citation Format: Elvin Wagenblast. Developmental dependency and metabolic vulnerabilities in NUP98-rearranged pediatric leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY34-01.