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.

间变性大细胞淋巴瘤 （ALCL） 是一种成熟的 T 细胞淋巴瘤，占儿童淋巴瘤的 10-15%。尽管观察到超过 90% 的儿科病例携带间变性淋巴瘤激酶 （ALK） 重排，导致 ALK 激酶表达异常，但存在显着的临床、形态学和生物学异质性。为了深入了解 ALK 阳性 ALCL （ALK+ ALCL） 内的基因组畸变和分子异质性，我们通过全外显子组测序、RNA 测序和 DNA 甲基化分析分析了 46 个儿科 ALK+ ALCLs。全外显子组测序发现，每个样本平均有 25 个 SNV/Indel 事件，在 DNA 损伤调节因子 （TP53、MDM4）、转录 （JUNB） 和表观遗传调节因子 （TET1、KMT2B、KMT2A、KMT2C、KMT2E） 中具有重复的遗传事件。基因表达和甲基化分析一致地将 ALK+ ALCL 分为两组，其特征是 ALK 表达水平不同。与 ALK 高组相比，ALK-low 组显示出与免疫反应、细胞因子信号传导和高甲基化为主模式相关的通路的富集，ALK 高组具有更频繁的拷贝数变化，并富含与细胞生长、增殖和代谢相关的通路。总而言之，这些发现表明儿科 ALK+ ALCL 中存在分子异质性，预测了不同的生物学机制，这可能为疾病发病机制提供新的见解并代表预后标志物。