Fatty acid metabolism shapes immune responses in chronic lymphocytic leukemia.

IF 9.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomarker Research Pub Date : 2025-03-12 DOI:10.1186/s40364-025-00753-7

Yang Zhang, Jun Ma, Peipei Li, Kang Lu, Yang Han, Xinting Hu, Xiaosheng Fang, Xin Wang, Ya Zhang

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Abstract

Background: Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabolism (FAM) in CLL, construct a related prognostic score, and investigate the regulatory role and mechanisms of FAM in CLL development.

Methods: Bulk RNA sequencing data from CLL patients and healthy controls were analyzed to identify differentially expressed fatty acid metabolic genes. FAM-score was constructed using Cox-LASSO regression and validated. Single-cell RNA sequencing was used to analyze the expression of key FAM genes in CLL immune cell subsets and investigate cellular communication. Functional assays, including cell viability, drug sensitivity, and oxygen consumption assays, were performed to assess the impact of fatty acid oxidation (FAO) inhibition on CLL cells.

Results: Three FAM-related genes (LPL, SOCS3, CNR1) were identified with independent prognostic significance to construct the risk score. The FAM-score demonstrated superior prognostic performance compared to the Binet stage and was associated with established clinical prognostic markers. Single-cell analysis revealed distinct expression patterns of LPL, SOCS3, and CNR1 across CLL immune cell subsets. Cellular communication analysis highlighted the regulatory role of distinct B cell and Treg subsets in the CLL microenvironment. CLL patients with high FAM-score displayed distinct immune infiltration patterns, with increased FAO pathway activity. Inhibition of FAO reduced CLL cell viability, synergistically enhanced the efficacy of the PI3K inhibitor idelalisib.

Conclusion: The present study constructed a prognostic risk score based on FAM gene expression, revealing related immune phenotypic differences and exploring the regulatory role of FAO in CLL development. Targeting fatty acid metabolism potentially modulates the CLL immune microenvironment and synergistically enhances the efficacy of PI3K inhibitors.

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脂肪酸代谢影响慢性淋巴细胞白血病的免疫反应。

背景：脂肪酸是慢性淋巴细胞白血病（CLL）进展过程中肿瘤细胞的重要能量来源。本研究旨在阐明CLL中脂肪酸代谢（FAM）的特点，构建相关预后评分，探讨FAM在CLL发生发展中的调控作用及机制。方法：分析来自CLL患者和健康对照者的大量RNA测序数据，以鉴定差异表达的脂肪酸代谢基因。采用Cox-LASSO回归构建fam评分并进行验证。利用单细胞RNA测序分析CLL免疫细胞亚群中关键FAM基因的表达并研究细胞通讯。功能测定，包括细胞活力、药物敏感性和耗氧量测定，评估脂肪酸氧化（FAO）抑制对CLL细胞的影响。结果：鉴定出3个fam相关基因（LPL、SOCS3、CNR1）具有独立预后意义，构建风险评分。与Binet期相比，fam评分表现出更好的预后表现，并与已建立的临床预后标志物相关。单细胞分析显示LPL、SOCS3和CNR1在CLL免疫细胞亚群中的表达模式不同。细胞通讯分析强调了不同的B细胞和Treg亚群在CLL微环境中的调节作用。高fam评分的CLL患者表现出明显的免疫浸润模式，FAO通路活性增加。抑制FAO降低CLL细胞活力，协同增强PI3K抑制剂ideelalisib的功效。结论：本研究构建了基于FAM基因表达的预后风险评分，揭示了相关的免疫表型差异，探讨了FAO在CLL发生发展中的调控作用。靶向脂肪酸代谢可能调节CLL免疫微环境，并协同增强PI3K抑制剂的疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomarker Research Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

15.80

自引率

1.80%

发文量

审稿时长

10 weeks

期刊介绍： Biomarker Research, an open-access, peer-reviewed journal, covers all aspects of biomarker investigation. It seeks to publish original discoveries, novel concepts, commentaries, and reviews across various biomedical disciplines. The field of biomarker research has progressed significantly with the rise of personalized medicine and individual health. Biomarkers play a crucial role in drug discovery and development, as well as in disease diagnosis, treatment, prognosis, and prevention, particularly in the genome era.