PO.CL01.21 · 临床研究
儿童白血病中融合特异性 RNA 生物标志物的计算机模拟发现
In silico discovery of fusion-specific RNA biomarkers in pediatric leukemias
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：儿童白血病仍是儿童癌症相关死亡的主要原因，其中融合驱动的亚型如 KMT2A 重排和 ETV6-RUNX1 白血病占高危病例的很大比例。尽管总生存率有所改善，但融合阳性白血病与较差的结局、次优的治疗反应和较高的复发风险相关。儿科肿瘤学中一个持续存在的挑战是复发诊断的延迟。尽管微小残留病检测和骨髓穿刺仍是诊断和监测的标准，但这些方法具有侵入性、成本高昂，且往往无法捕捉动态的致癌变化。由异常基因融合形成的致癌嵌合转录因子（OCTF）是许多儿童白血病中的关键分子驱动因素。新兴的转录组数据表明，OCTF 驱动的肿瘤产生称为新生基因（neogene）的独特非经典 RNA 转录本，其可能具有高度癌症特异性，并代表一类有前景的新型 RNA 生物标志物。本研究的目的是在融合驱动的儿童白血病中识别和表征新生基因转录本，以评估其作为亚型特异性 RNA 生物标志物用于早期检测和疾病监测的潜力。
方法：我们构建了一个模块化转录组流程，以识别融合驱动的儿童白血病中的新生基因候选。使用 STAR（剪接转录本参考比对）将公开可用的 RNA-seq 数据集比对到人类参考基因组，随后使用 Scallop 进行转录本组装。通过 Gffcompare 识别未注释的转录本并在归一化后进行定量。候选新生基因基于新颖性、跨样本复现性和生物学合理性进行过滤。对非白血病融合阳性和融合阴性癌症以及正常组织进行平行定量，以评估新生基因的特异性。
结果：分析了七种儿童白血病亚型：AML、AMoL、APL、CML、T-ALL 和 preB/proB 细胞白血病。初步分析显示，每种亚型均表现出独特的新生基因特征，这在非白血病融合阳性癌症（尤因肉瘤、横纹肌肉瘤和促结缔组织增生性小圆细胞肿瘤）或常见的融合阴性儿童恶性肿瘤（神经母细胞瘤、肾母细胞瘤和肝母细胞瘤）中未观察到。新生基因位点的染色质可及性和组蛋白修饰标志物为活跃转录提供了证据，并支持转录本的生物学相关性。
结论：计算机模拟发现支持融合驱动的儿童白血病中存在亚型特异性新生基因特征。这些转录本可作为早期检测、亚型分类和治疗监测的新型生物标志物。进一步的验证正在进行中，以评估其临床效用和转化潜力。
查看英文原文 English abstract
Purpose: Pediatric leukemia remains a leading cause of cancer-related mortality in children, with fusion-driven subtypes such as KMT2A-rearranged and ETV6-RUNX1 leukemias accounting for a significant proportion of high-risk cases. Despite improvements in overall survival, fusion-positive leukemias are associated with poorer outcomes, suboptimal therapeutic response, and elevated relapse risk. A persistent challenge in pediatric oncology is delayed relapse diagnosis. Although minimal residual disease testing and bone marrow aspiration remain standard for diagnosis and monitoring, these approaches are invasive, costly, and often fail to capture dynamic oncogenic changes. Oncogenic chimeric transcription factors (OCTFs), formed by abnormal gene fusions, are key molecular drivers in many pediatric leukemias. Emerging transcriptomic data suggest that OCTF-driven tumors produce unique noncanonical RNA transcripts termed neogenes which may be highly cancer-specific and represent a promising new class of RNA biomarkers. The purpose of this study is to identify and characterize neogene transcripts in fusion-driven pediatric leukemias with the goal of evaluating their potential as subtype-specific RNA biomarkers for early detection and disease monitoring .
Methods: We assembled a modular transcriptome pipeline to identify neogene candidates in fusion-driven pediatric leukemias. Publicly available RNA-seq datasets were aligned to the human reference genome using STAR (Spliced Transcripts Alignment to a Reference), followed by transcript assembly with Scallop. Unannotated transcripts were identified via Gffcompare and quantified post-normalization. Candidate neogenes were filtered based on novelty, cross-sample recurrence, and biological plausibility. Parallel quantification of non-leukemic fusion-positive and fusion-negative cancers and normal tissues were performed to assess for neogene specificity.
Results: Seven pediatric leukemia subtypes were profiled: AML, AMoL, APL, CML, T-ALL, and preB/proB-cell leukemia. Preliminary analyses reveal that each subtype exhibits a distinct neogene signature not observed in non-leukemic fusion-positive cancers (Ewing sarcoma, rhabdomyosarcoma, and Desmoplastic Small Round Cell Tumor) or in common fusion-negative pediatric malignancies (neuroblastoma, nephroblastoma, and hepatoblastoma). Chromatin accessibility and histone modification markers at neogene loci provide evidence for active transcription and supports biological relevance of transcripts.
Conclusion: In silico findings support the existence of subtype-specific neogene signatures in fusion-driven pediatric leukemias. These transcripts may serve as novel biomarkers for early detection, subtype classification, and treatment monitoring. Further validation is underway to assess clinical utility and translational potential.
利益披露 Disclosure
E. Chang, None..
S. Lee, None.