Shaw Timothy I, Pounds Stanley, Cao Xueyuan, Ma Jing, Palacios Gustavo, Mason John, Perkins Sherrie, Wu Gang, Fan Yiping, Wang Jian, Zhou Xin, Obermayer Alyssa, Kinney Marsha C, Kraveka Jacqueline, Gross Thomas, Sandlund John, Zhang Jinghui, Mullighan Charles, Lim Megan S, Leventaki Vasiliki
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
Leukemia. 2025 Jan;39(1):199-210. doi: 10.1038/s41375-024-02468-4. Epub 2024 Nov 26.
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%的儿科病例存在间变性淋巴瘤激酶（ALK）重排，导致ALK激酶异常表达，但仍存在显著的临床、形态学和生物学异质性。为了深入了解ALK阳性ALCL（ALK+ ALCL）中的基因组畸变和分子异质性，我们通过全外显子测序、RNA测序和DNA甲基化分析对46例儿科ALK+ ALCL进行了分析。全外显子测序发现每个样本平均有25个单核苷酸变异/插入缺失事件，在DNA损伤调节因子（TP53、MDM4）、转录调节因子（JUNB）和表观遗传调节因子（TET1、KMT2B、KMT2A、KMT2C、KMT2E）中存在反复出现的遗传事件。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高表达组相比，ALK低表达组显示出与免疫反应、细胞因子信号传导相关的通路富集以及高甲基化为主的模式，ALK高表达组有更频繁的拷贝数变化，并且富含与细胞生长、增殖和代谢相关的通路。总之，这些发现表明儿科ALK+ ALCL中存在分子异质性，预示着不同的生物学机制，这可能为疾病发病机制提供新的见解并代表预后标志物。
