LIN28B hypomethylation drives oncogenic signaling and stratifies poor prognosis in juvenile myelomonocytic leukemia.

Abstract

Background: LIN28B, an oncofetal RNA-binding protein regulating stem cell self-renewal and oncogenic signaling via let-7 miRNA suppression, is implicated in diverse malignancies but remains poorly characterized in juvenile myelomonocytic leukemia (JMML). Despite its reported overexpression in approximately 50% of JMML cases, the epigenetic mechanisms driving LIN28B dysregulation and its clinical relevance for risk stratification are undefined. Therefore, this study aimed to elucidate the epigenetic regulation of LIN28B in JMML, and determine its potential as a biomarker for risk stratification.

Methods: We analyzed LIN28B expression and methylation in 24 JMML patients and validated the methylation classification in an independent validation cohort (n=62). Gene Set Enrichment Analysis (GSEA) of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was conducted to find out the potential mechanisms underlying the differentially expressed LIN28B.

Results: Among 24 JMML patients, more than 58% showed overexpression of LIN28B, with the majority exhibiting hypomethylation in a newly identified upstream promoter region. Patients with LIN28B-positive showed concurrent upregulation of WT1, POU1F1 and GATA5, downregulation of HEY1 and enriched for cell cycle pathways. Hierarchical clustering identified a high-methylation (HM) subgroup enriched for adverse features: age >2 years, PTPN11 mutations, and hypermethylation phenotypes. In an independent cohort, the HM patients demonstrated inferior 5-year overall survival (OS, 49.2% vs. 87.0%) and event-free survival (EFS, 40.1% vs. 87.0%) versus low-methylation counterparts.

Conclusions: LIN28B activation via promoter hypomethylation defines a high-risk JMML subgroup with cell cycle. Methylation-based stratification predicts survival, positioning LIN28B as a therapeutic target.