Histone Methyltransferase and Demethylase Gene in Pediatric Acute Lymphoblastic Leukemia: A Molecular Insights
DOI:
https://doi.org/10.48048/tis.2026.11952Keywords:
Epigenetic regulation, Gene mutation, Histone demethylase, Histone methyltransferase, Pediatric ALLAbstract
Genetic factors driving the development of pediatric Acute Lymphoblastic Leukemia (ALL) remain incompletely understood. While epigenetic dysregulation through histone methyltransferases and demethylases has emerged as a critical oncogenic mechanism, their specific contributions to pediatric ALL require systematic investigation. In this study, we systematically investigated genetic variants in histone methyltransferases and demethylase found in top 50 mutated genes from TARGET ALL Phase 2 cohort. Single nucleotide variations were functionally annotated using PredictSNP and I-Mutant2.0, followed by survival analysis and pathway enrichment studies comparing mutated versus wild-type patients. KMT2D, NSD2, SETD2, EZH2 (methyltransferases), and KDM6A (demethylase), ranked among the most frequently mutated genes. Multiple frameshift and nonsense mutations were identified in these genes, likely resulting in truncated proteins and loss of function. Critically, missense variants in EZH2 (F145C, R679C, P132T, D652G, A576D, S280C, Y728H, C566S), KDM6A (G1242D), NSD2 (E1099K, D1125H), and SETD2 (G2170D, R1592Q) were computationally predicted as deleterious and destabilizing. Although survival analysis revealed no statistically significant differences (p = 0.37), mutation carriers exhibited a 44% increased mortality risk, suggesting clinical relevance despite limited sample size (n = 35). Gene set enrichment analysis of differentially expressed genes revealed significant activation of hematopoietic cell lineage pathways in mutated patients. Our findings underscore the importance of histone methyltransferase and demethylase gene variants in pediatric ALL, particularly novel mutations affecting protein function and stability that remain poorly characterized in the literature. This study identifies candidate mutations that warrant further functional and clinical investigation for their role in disease progression and therapeutic targeting.
HIGHLIGHTS
- KMT2D, NSD2, SETD2, EZH2, and KDM6A are identified among the top 50 most frequently mutated genes in pediatric ALL
- KMT2D exhibits the highest mutational burden in pediatric ALL, predominantly harboring frameshift and nonsense alterations
- KMT2D, NSD2, SETD2, EZH2, and KDM6A genes show consensus deleterious predictions across multiple in silico tools, with 18 mutations representing high-priority candidates for experimental validation
- Structural stability analysis reveals critical destabilizing mutations in EZH2 (F145C, R679C, P132T, D652G, A576D, S280C, Y728H, C566S), KDM6A (G1242D), NSD2 (E1099K, D1125H), and SETD2 (G2170D, R1592Q)
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