Mitochondrial Genomic Alterations in Pediatric Acute Lymphoblastic Leukemia: Implications for Methotrexate-Induced...

Methotrexate (MTX)-induced neurotoxicity is a serious complication in pediatric acute lymphoblastic leukemia (ALL), with observed ethnic disparities in risk. To investigate the role of mitochondrial DNA (mtDNA) variation, we performed whole mtDNA sequencing in 94 children with ALL, including 62 Hispanic patients. We identified 1294 mtDNA variants, including 12.4% novel variants, with MT-ND5 and the D-loop representing major variant hotspots. Gene-based analyses identified significant associations of MT-ND6 and MT-ND2 with MTX neurotoxicity after multiple testing correction. Heteroplasmy was more frequent in affected patients, and predictive models incorporating mtDNA variants improved discrimination (AUC = 0.78) compared with clinical factors alone. These findings suggest that mtDNA variation, particularly involving Complex I genes, may contribute to MTX neurotoxicity and support its potential utility for risk stratification, while requiring validation in independent cohorts.