CpG island methylator phenotype classification improves risk assessment in pediatric T-cell Acute Lymphoblastic Leukemia [methylation array]

ABSTRACT: Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy arising from T-cell precursors, currently treated by intensive chemotherapies with substantial side effects. Novel biomarkers are required to guide therapy decisions, improve diagnostics, and introduce precision medicine. Despite efforts, currently identified biomarkers such as genetics, immunophenotype, and transcriptomics have not efficiently stratified pediatric T-ALL patients. DNA methylation has emerged as a promising novel biomarker in T-ALL. This study aimed to validate the prognostic relevance of CpG island methylator phenotype (CIMP) risk stratification in a large pediatric T-ALL patient cohort (n=192) treated by the NOPHO ALL2008 protocol. This study confirms that combining CIMP classification at diagnosis with measurable residual disease (MRD) at treatment day 15 or 29 improves outcome prediction (cumulative incidence of relapse (CIR) and overall survival (OS), p<0.001). A poor prognosis subgroup represented by CIMP low/D29 MRD≥0.1% (n=38) showed pCIR5yr=29.0% (95%-CI 16.0-44.0), and pOS5yr=59.7% (95%-CI 45.7-77.9). Conversely, a good prognosis subgroup represented by CIMP high/D29 MRD<0.1% (n=57) with pCIR5yr=0% (95%-CI 0-0), and pOS5yr=98.2% (95%-CI 94.8-100.0). Notably, all late relapses (>5 years post-diagnosis, n=4) showed a CIMP low profile at diagnosis. Furthermore, CIMP biological subgroups were associated with transcriptome profiles in T-ALL biology, genomic aberrations, epigenetic age, and mitotic history, suggesting distinct routes for leukemia development. In conclusion, integrating MRD assessment with the novel CIMP classification biomarker has the potential to improve risk stratification in pediatric T-ALL and guide future therapeutic decisions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272021 | GEO | 2025/01/29

REPOSITORIES: GEO