FOXN3-AS1:急性髓性白血病的候选预后标记和具有免疫治疗意义的表观遗传靶标

IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Fangfang Ge, Yulu Wang, Peng Chen, Amit Sharma, Xiaoli Huang, Tikam Chand Dakal, Zifeng Wang, Ulrich Jaehde, Markus Essler, Matthias Schmid, Ingo G H Schmidt-Wolf
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引用次数: 0

摘要

目的:我们重点研究了FOXN3基因,并选择了其反义转录本(FOXN3-AS1),以研究其在急性髓性白血病(AML)中的潜在参与:背景:一些整合的多组学数据集拓展了癌症研究的视野。随着新的高通量技术的出现,大量非编码 RNA 被证实参与了不同类型血液恶性肿瘤的发病机制:我们用急性髓细胞白血病患者的骨髓标本进行了定量聚合酶链反应(qPCR)实验验证。然后,利用Kaplan-Meier(KM)曲线和Receiver Operating Characteristic(ROC)曲线证实了TCGA数据库中FOXN3-AS1与AML患者预后的相关性。利用斯皮尔曼相关分析法研究 FOXN3-AS1 表达与基因突变、免疫和免疫功能之间的相关性。为了探索 FOXN3-AS1 与 DNMT1 蛋白之间的物理和功能相互作用,我们使用了爱荷华州立大学的 RPISeq 网络工具。随后,我们进行了 qPCR 实验,检测 5AzaC(DNMT1 抑制剂)对 FOXN3-AS1 表达的 AML 细胞系(THP1 和 OCI-AML3)的影响。我们利用 "OncoPredict "R软件包和药物敏感性基因组学(GDSC)数据库来预测表达FOXN3-AS1的AML患者的药物反应:我们利用临床样本观察到,与健康对照组相比,AML 患者的 FOXN3-AS1 表达明显上调。TCGA数据库显示,FOXN3-AS1高表达与不良预后有关。在我们随后的分析中,FOXN3-AS1 高表达组中发现了对急性髓细胞性白血病患者预后影响较差的基因,进一步证实了这一关系。FOXN3-AS1表达水平较高的急性髓细胞性白血病患者对免疫疗法的反应可能不如表达水平较低的患者。此外,我们通过计算预测了 FOXN3- AS1 与 DNMT1 蛋白的相互作用,并通过实验证实 DNMT1i(GSK-3484862)会影响 FOXN3-AS1 的表达水平。我们还发现,化疗药物(5-氟尿嘧啶、顺铂、达克替尼、沙必替尼、替莫唑胺、乌利克替尼、维诺雷滨、鲁索利替尼、奥西莫替尼和顺铂)在FOXN3-AS1高表达水平的急性髓细胞性白血病患者中显示出良好的反应:我们的候选方法确定了FOXN3-AS1作为急性髓细胞性白血病生存预后指标的潜在免疫相关作用。我们对FOXN3-AS1/DNMT1串扰的初步观察表明,有必要对急性髓细胞性白血病的免疫治疗方法进行更深入的研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
FOXN3-AS1: A Candidate Prognostic Marker and Epigenetic Target with Immunotherapeutic Implications in Acute Myeloid Leukemia.

Aim: We focused on the FOXN3 gene and selected its antisense transcripts (FOXN3-AS1) to investigate its potential involvement in acute myeloid leukemia (AML).

Background: Several integrated multi-omics datasets have expanded the horizons of the cancer landscape. With the emergence of new high-throughput technologies, a large number of non-coding RNAs have been confirmed to be involved in the pathogenesis of different types of hematological malignancies.

Methods: We conducted experimental validation using quantitative polymerase chain reaction (qPCR) with bone marrow specimens from AML patients. Then, Kaplan-Meier (KM) and Receiver Operating Characteristic (ROC) curves were used to substantiate the prognostic association between FOXN3-AS1 and AML patients within the TCGA database. Correlation between FOXN3-AS1 expression and gene mutation, immune, and immune function using Spearman correlation analysis. To explore the physical and functional interaction between FOXN3-AS1 and the DNMT1 protein, we utilized the RPISeq web tool from Iowa State University. Subsequently, we performed qPCR experiments to test the effect of 5AzaC (DNMT1 inhibitor) on FOXN3-AS1 expression AML cell lines (THP1 and OCI-AML3). We leveraged the "OncoPredict" R package in conjunction with the Genomics of Drug Sensitivity (GDSC) database to predict drug response in AML patients expressing FOXN3-AS1.

Results: We observed a significant upregulation of FOXN3-AS1 expression in AML patients compared to healthy controls using clinical samples. The TCGA database revealed an association between high FOXN3-AS1 expression and adverse prognosis. In our subsequent analysis, genes with poor prognostic implications in AML patients were exclusively identified in the FOXN3-AS1 high-expression group, further corroborating this relationship. AML patients with higher FOXN3-AS1 expression levels may respond less optimally to immunotherapy than patients with lower levels. Besides, we computationally predicted the interaction of FOXN3- AS1 and DNMT1 protein and experimentally confirmed that DNMT1i (GSK-3484862) affects the expression level of FOXN3-AS1. We also found that the chemotherapy drugs (5-Fluorouralic, Cisplatin, Dactolisib, Sapitinib, Temozolomide, Ulixertinib, Vinorelbine, Ruxolitinib, Osimertinib and Cisplatin) showed favorable responses in AML patients with high FOXN3-AS1 expression levels.

Conclusion: Our candidate approach identifies FOXN3-AS1 as a prognostic indicator of survival in AML with a potential immune-related role. The preliminary observations we made on FOXN3-AS1/DNMT1 crosstalk warrant more in-depth invested immunotherapeutic approaches in AML.

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来源期刊
Current medicinal chemistry
Current medicinal chemistry 医学-生化与分子生物学
CiteScore
8.60
自引率
2.40%
发文量
468
审稿时长
3 months
期刊介绍: Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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