Lai Junchen, Miao Yan, Qin Xia, Lin Yuchen, Luo Chengjuan, Luo Changying, Wang Xinan, Zhou Chen, Chen Jing
Department of Hematopoietic Stem Cell Transplantation, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Laboratory Department II, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Transl Pediatr. 2025 Jul 31;14(7):1541-1552. doi: 10.21037/tp-2025-228. Epub 2025 Jul 28.
, an oncofetal RNA-binding protein regulating stem cell self-renewal and oncogenic signaling via let-7 miRNA suppression, is implicated in diverse malignancies but remains poorly characterized in juvenile myelomonocytic leukemia (JMML). Despite its reported overexpression in approximately 50% of JMML cases, the epigenetic mechanisms driving dysregulation and its clinical relevance for risk stratification are undefined. Therefore, this study aimed to elucidate the epigenetic regulation of in JMML, and determine its potential as a biomarker for risk stratification.
We analyzed expression and methylation in 24 JMML patients and validated the methylation classification in an independent validation cohort (n=62). Gene Set Enrichment Analysis (GSEA) of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was conducted to find out the potential mechanisms underlying the differentially expressed .
Among 24 JMML patients, more than 58% showed overexpression of LIN28B, with the majority exhibiting hypomethylation in a newly identified upstream promoter region. Patients with -positive showed concurrent upregulation of and , downregulation of and enriched for cell cycle pathways. Hierarchical clustering identified a high-methylation (HM) subgroup enriched for adverse features: age >2 years, mutations, and hypermethylation phenotypes. In an independent cohort, the HM patients demonstrated inferior 5-year overall survival (OS, 49.2% 87.0%) and event-free survival (EFS, 40.1% 87.0%) versus low-methylation counterparts.
activation via promoter hypomethylation defines a high-risk JMML subgroup with cell cycle. Methylation-based stratification predicts survival, positioning as a therapeutic target.
LIN28B是一种癌胚RNA结合蛋白，通过抑制let-7 miRNA调节干细胞自我更新和致癌信号传导，与多种恶性肿瘤有关，但在青少年骨髓单核细胞白血病（JMML）中的特征仍不清楚。尽管报道约50%的JMML病例中LIN28B过表达，但驱动其失调的表观遗传机制及其在风险分层中的临床相关性尚不清楚。因此，本研究旨在阐明JMML中LIN28B的表观遗传调控，并确定其作为风险分层生物标志物的潜力。
我们分析了24例JMML患者中LIN28B的表达和甲基化情况，并在一个独立的验证队列（n=62）中验证了甲基化分类。进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）的基因集富集分析（GSEA），以找出差异表达的LIN28B潜在机制。
在24例JMML患者中，超过58%表现出LIN28B过表达，大多数在新发现的上游启动子区域表现出低甲基化。LIN28B阳性患者同时表现出CCND2和MYC的上调、let-7的下调以及细胞周期途径的富集。层次聚类确定了一个高甲基化（HM）亚组，其具有不良特征：年龄>2岁、NRAS突变和高甲基化表型。在一个独立队列中，与低甲基化患者相比，HM患者的5年总生存率（OS，49.2%对87.0%）和无事件生存率（EFS，40.1%对87.0%）较差。
通过启动子低甲基化激活LIN28B定义了一个具有细胞周期的高危JMML亚组。基于甲基化的分层可预测生存率，将LIN28B定位为治疗靶点。
