Faculty, Staff and Student Publications

Language

English

Publication Date

1-1-2025

Journal

Leukemia

DOI

10.1038/s41375-024-02468-4

PMID

39592809

PMCID

PMC12771790

PubMedCentral® Posted Date

1-7-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL (ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by differential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK-high group, which had more frequent copy number changes and was enriched with pathways associated with cell growth, proliferation, and metabolism. Altogether, these findings suggest that there is molecular heterogeneity within pediatric ALK+ ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.

Keywords

Humans, Lymphoma, Large-Cell, Anaplastic, Anaplastic Lymphoma Kinase, Child, Female, Male, Adolescent, Child, Preschool, DNA Methylation, Genomics, Genetic Heterogeneity, Biomarkers, Tumor, Exome Sequencing, Prognosis, Infant, Gene Expression Profiling

Published Open-Access

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