Significance of PPARA as a Treatment Target for Chronic Lymphocytic Leukemia.

IF 3.5 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL PPAR Research Pub Date : 2023-01-01 DOI:10.1155/2023/8456833
Xixi Xiang, Fu Li, Sha Zhou, Yunjing Zeng, Xiaojuan Deng, Hongyang Zhang, Jiali Li, Hongyun Liu, Jun Rao, Lei Gao, Cheng Zhang, Qin Wen, Li Gao, Xi Zhang
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Abstract

Peroxisome proliferator-activated receptor alpha (PPARA) has been suggested as a therapeutic target for chronic lymphocytic leukemia (CLL). However, the underlying molecular mechanism remains largely unclear. In this study, we analyzed DNA next-generation sequencing (NGS) data and clinical information from 86 CLL patients to identify gene markers related to treatment-free survival (TFS) length. We then constructed a genetic network that includes CLL promoters, treatment targets, and TFS-related marker genes. To assess the significance of PPARA within the network, we utilized degree centrality (DC) and pathway enrichment score (EScore). Clinical and NGS data revealed 10 TFS length-related gene markers, including RPS15, FOXO1, FBXW7, KMT2A, NOTCH1, GNA12, EGR2, GNA13, KDM6A, and ATM. Through literature data mining, 83 genes were identified as CLL upstream promoters and treatment targets. Among them, PPARA exhibited a stronger connection to CLL and TFS-related gene markers, as evidenced by its ranking at No. 13 based on DC, compared to most of the other promoters (>84%). Additionally, PPARA co-functions with 70 out of 92 in-network genes in various functional pathways/gene groups related to CLL pathology, such as regulation of cell adhesion, inflammation, reactive oxygen species, and cell differentiation. Based on our findings, PPARA is considered one of the critical genes within a large genetic network that influences the prognosis and TFS of CLL through multiple pathogenic pathways.

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PPARA作为慢性淋巴细胞白血病治疗靶点的意义。
过氧化物酶体增殖物激活受体α (PPARA)已被认为是慢性淋巴细胞白血病(CLL)的治疗靶点。然而,潜在的分子机制在很大程度上仍不清楚。在这项研究中,我们分析了来自86名CLL患者的DNA下一代测序(NGS)数据和临床信息,以确定与无治疗生存期(TFS)长度相关的基因标记。然后,我们构建了一个包括CLL启动子、治疗靶点和tfs相关标记基因的遗传网络。为了评估PPARA在网络中的重要性,我们使用了度中心性(DC)和通路富集评分(EScore)。临床和NGS数据显示10个TFS长度相关基因标记,包括RPS15、fox01、FBXW7、KMT2A、NOTCH1、GNA12、EGR2、GNA13、KDM6A和ATM。通过文献数据挖掘,鉴定出83个基因为CLL上游启动子和治疗靶点。其中,与大多数其他启动子相比,PPARA与CLL和tfs相关的基因标记具有更强的联系,其基于DC的排名为第13位(>84%)。此外,在与CLL病理相关的各种功能通路/基因群中,PPARA与92个网络基因中的70个共同起作用,如细胞粘附、炎症、活性氧和细胞分化的调节。根据我们的研究结果,PPARA被认为是通过多种致病途径影响CLL预后和TFS的大型遗传网络中的关键基因之一。
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来源期刊
PPAR Research
PPAR Research MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.20
自引率
3.40%
发文量
17
审稿时长
12 months
期刊介绍: PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research focusing on mechanisms involved in the activation of peroxisome proliferator-activated receptors (PPARs), as well as their role in the regulation of cellular differentiation, development, energy homeostasis and metabolic function. The journal also welcomes preclinical and clinical trials of drugs that can modulate PPAR activity, with a view to treating chronic diseases and disorders such as dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, and obesity.
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