Aberrant overexpression of m6A writer and reader genes in pediatric B-Cell Acute Lymphoblastic Leukemia (B-ALL).

BACKGROUND: m6A modification, regulated by writers (METTL3, METTL14), erasers (ALKBH5, FTO), and readers (IGF2BPs), is implicated in various cancers, including leukemias. METHODS: In our study, we examined a cohort of 227 pediatric B-ALL patients (152 primary and 75 relapsed) and assessed the expression profiles of m6A machinery genes, including both writers and erasers, as well as the IGF2BP RNA-binding proteins, which are known as m6A readers. We also quantified the absolute percentage of m6A (m6A%). The correlation between m6A machinery gene expression and patient prognosis was studied using univariate and multivariate analyses. RESULTS: Our analysis revealed a significant upregulation of m6A writers (METTL3 and METTL14), erasers (FTO), and m6A readers (IGF2BPs 1 and 3) in B-ALL patients, both in the primary and relapsed groups. m6A% levels were markedly higher in B-ALL samples than in controls. Multivariate analysis revealed that the expression of IGF2BP3, METTL3, and FTO genes, independently predicted lower overall survival and event-free survival in primary B-ALL patients. CONCLUSIONS: Despite the collective dysregulation of the m6A machinery, the writers and readers appear to have a more dominant phenotype, as evidenced by the significantly elevated m6A% levels. This is the first study to analyze and establish the role of m6A machinery gene expression and its correlation with survival outcomes in a large group of B-ALL patients. These findings could aid in the development of new therapeutics targeting the m6A machinery and help predict relapse in pediatric B-ALL patients.