Genomic analyses have redefined the molecular subgrouping of pediatric acute lymphoblastic leukemia (ALL). Molecular subgroups guide risk-stratification and targeted therapies, but outcomes of recently identified subtypes are often unclear, owing to limited cases with comprehensive profiling and cross-protocol studies. We developed a machine learning tool (ALLIUM) for the molecular subclassification of ALL in retrospective cohorts as well as for up-front diagnostics. ALLIUM uses DNA methylation and gene expression data from 1131 Nordic ALL patients to predict 17 ALL subtypes with high accuracy. ALLIUM was used to revise and verify the molecular subtype of 280 cases with undefined/B-other molecular phenotype, resulting in a single revised subtype for 85.4% of these cases. Our study shows the power of combining DNA methylation and gene expression data for resolving ALL subtypes and provides the first comprehensive population-based retrospective cohort study of molecular subtype frequencies in the Nordic countries, identifying subgroups with differential survival outcomes.

The authors have declared no competing interest.

This study was funded by the Swedish Research Council (2019-01976), the Swedish Cancer Society (CAN2018-623 and CAN2022-2395), the Swedish Childhood Cancer Foundation (PR2017-0023 and PR2019-0046), the Göran Gustafsons Foundation, the Jane and Aatos Erkko Foundation and the Academy of Finland (#321550).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the regional ethics board in Uppsala, Sweden and by the Nordic Society of Paediatric Haematology and Oncology (NOPHO) Scientific Committee (Study #56).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.