Altered Expression of m6A-Associated Genes Is Linked with Poor Prognosis in Pediatric Acute Myeloid Leukemia Patients

The dysregulation of m6A-related genes recognized as 'writers', 'readers', and 'erasers' is reported to be involved in the initiation, progression, and drug resistance of acute myeloid leukemia (AML). In the present study, we investigated the expression levels of various readers, writers, and erasers in pediatric AML patients. Additionally, we categorized the patients according to the molecular subtyping of common mutations and recurrent fusions and correlated the expression of m6A-associated genes with different molecular subtypes and evaluated their prognostic and clinical implications. A total of fifty-seven patients with pediatric de novo AML were enrolled in the study. The study cohort consisted of 41 males and 16 females with a median age of 7 years (range 1 to 12 years). A high expression of m6A RNA modification complex genes was noted in AML patients. Among the writers, <i>METTL3</i> and <i>METTL14</i> were found to be upregulated in 19 and 17 patients, the readers <i>YTHDF1</i> and <i>YTHDF2</i> showed higher expression in 6 and 10 patients, while a high expression of erasers <i>FTO</i> and <i>ALKBH5</i> was found in 28 patients and 1 patient, respectively. Further, the expression of m6A regulators showed a significant association with genetic alterations including <i>FLT3-ITD</i>, <i>RBM15::MKL</i> fusions and <i>NPM1</i> mutations. Additionally, while evaluating the prognostic implications, both the readers <i>YTHDF1</i> and <i>YTHDF2</i> showed a significant correlation with TLC at diagnosis (<i>p</i> < 0.05). Further, Kaplan-Meier estimation showed a poor event-free survival in cases with the overexpression of <i>YTHDF1</i> (log-rank <i>p</i> = 0.028). Additionally, we noted a strong correlation between <i>YTHDF1</i> overexpression and treatment-related mortality (log-rank <i>p</i> < 0.001), and a nearly significant correlation with <i>YTHDF2</i> expression in such patients (log-rank <i>p</i> = 0.053) at a median follow-up of 8 months. Thus, our data suggest that m6A genes, especially readers <i>YTHDF1</i> and <i>YTHDF2</i>, are involved in the disease prognosis of AML and probably function in an integrated manner with other m6A-modifying genes to subsequently play a role in AML pathogenesis.