Robust genetic characterization of pediatric acute myeloid leukemia (AML) has demonstrated that fusion oncogenes are highly prevalent drivers of AML leukemogenesis in young children. Identification of fusion oncogenes associated with adverse outcomes has facilitated risk stratification of patients, although successful development of precision medicine approaches for most fusion-driven AML subtypes have been historically challenging. This knowledge gap has been in part due to difficulties in targeting structural alterations involving transcription factors and in identification of a therapeutic window for selective inhibition of the oncofusion without deleterious effects upon essential wild-type proteins. Herein, we discuss the current molecular landscape and functional characterization of 3 of the most lethal childhood AML fusion-oncogene driven subtypes harboring KMT2A, NUP98, or CBFA2T3::GLIS2 rearrangements. We further review early-phase clinical trial data of novel targeted inhibitors and immunotherapies that have demonstrated initial success specifically for children with these poor-prognosis genetic subtypes of AML and provide appreciable optimism to improve clinical outcomes in the future.
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May 29, 2025
Precision medicine for high-risk gene fusions in pediatric AML: a focus on KMT2A, NUP98, and GLIS2 rearrangements Available to Purchase
Grace Egan,
Grace Egan
1Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada
2Department of Paediatrics, University of Toronto, Toronto, ON, Canada
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Sarah K. Tasian
Sarah K. Tasian
3Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
4Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
5Princess Máxima Center for Paediatric Oncology, Utrecht, The Netherlands
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Blood (2025) 145 (22): 2574–2586.
Article history
Submitted:
November 6, 2024
Accepted:
December 30, 2024
First Edition:
January 14, 2025
Citation
Grace Egan, Sarah K. Tasian; Precision medicine for high-risk gene fusions in pediatric AML: a focus on KMT2A, NUP98, and GLIS2 rearrangements. Blood 2025; 145 (22): 2574–2586. doi: https://doi.org/10.1182/blood.2024026598
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