文章：

慢性淋巴细胞白血病的转录组聚类：基于布鲁顿酪氨酸激酶表达水平的分子亚型

Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levels

原文发布日期：2024-12-18

DOI: 10.1038/s41408-024-01196-3

类型: Article

开放获取: 是

英文摘要：

Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progression. We hypothesized that transcriptome and proteome may identify functional omics associated with CLL nosology. As a test cohort, we utilized publicly available treatment-naïve CLL transcriptomics data (n = 130) and did consensus clustering that identified BTK-expression-based clusters. The BTK-High and BTK-Low clusters were validated in public and our in-house databases (n = >550 CLL patients). To associate with functional relevance, we took samples from 151 previously treated patient with CLL and analyzed them using RNA sequencing and reverse-phase protein array. Transcript levels were strongly correlated with BTK protein levels. BTK-High subtype showed increased CCL3/CCL4 levels and disease burden such as high WBC. BTK-Low subtype showed down-regulated mRNA/proteins of DNA-repair pathway and increased DNA-damage-response, which may have contributed to enrichment of inflammatory pathway. BTK-Low subtype was rich in proapoptotic gene and protein expression and relied less on BCR pathway. High-BTK subgroup was enriched in replication/repair pathway and transcription machinery. In conclusion, profiling of 5 datasets of ~700 patients revealed unique BTK-associated expression clusters in CLL.
 

摘要翻译： 

历史上，慢性淋巴细胞白血病（CLL）的预后评估主要依赖于反映疾病负荷的临床分期。随后，染色体异常和基因组学研究提示了数种与治疗反应相关的CLL亚型。基因表达谱数据揭示了与CLL进展相关的信号通路。我们假设转录组和蛋白质组可能识别出与CLL疾病分类相关的功能性组学特征。作为测试队列，我们利用公开的初治CLL转录组学数据（n=130），通过共识聚类识别出基于BTK表达水平的聚类分组。这种BTK高表达与低表达集群在公共数据库及我们内部数据库（n>550例CLL患者）中得到验证。为探究其功能相关性，我们对151例既往接受过治疗的CLL患者样本进行RNA测序和反相蛋白阵列分析。结果显示转录水平与BTK蛋白水平呈强相关。BTK高表达亚型表现出CCL3/CCL4水平升高及高白细胞计数等疾病负荷特征。BTK低表达亚型则显示DNA修复通路的mRNA/蛋白质下调及DNA损伤应答增强，这可能促进炎症通路的富集。该亚型富含促凋亡基因和蛋白表达，且较少依赖B细胞受体通路。高BTK亚组在复制/修复通路及转录机制方面表现富集。综上所述，通过对约700例患者的5组数据集进行分析，我们发现了CLL中独特的BTK相关表达集群。

原文链接：

Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levels