FLT3 mutation-related immune checkpoint molecule absent in melanoma 2 (AIM2) contributes to immune infiltration in pediatric and adult acute myeloid leukemia: evidence from bioinformatics analysis.

IF 1.5 4区 医学 Q4 ONCOLOGY
Translational cancer research Pub Date : 2024-11-30 Epub Date: 2024-11-27 DOI:10.21037/tcr-24-1403
Jing Zhao, Yue Cui, Hua Zhou, Dongming Zhou, Zhiping Che, Ning Zhang, Qi Yun, João Agostinho Machado-Neto, Daniela Damiani, Lika'a Fasih Y Al-Kzayer, Rohan Kulkarni, Meng Gu
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引用次数: 0

Abstract

Background: The use of FMS-like tyrosine kinase 3 (FLT3) as a crucial target for kinase inhibitors is well established, but its association with immune infiltration remains unclear. This study aimed to explore the relationship between FLT3 mutations and immune checkpoint molecules (ICMs) in patients with acute myeloid leukemia (AML).

Methods: The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used to identify the ICMs associated with FLT3 mutations. A Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were conducted to analyze the signaling pathways related to the ICMs. The single-sample GSEA (ssGSEA), Cibersort, and estimate algorithms were used to assess immune cell infiltration in AML.

Results: Absent in melanoma 2 (AIM2) exhibits elevated expression levels in AML patients harboring FLT3 mutation, contributing significantly to the progress of AML and establishing of an immunosuppressive microenvironment. AIM2 expression significantly correlated with sensitivity of clinically relevant drugs in ex vivo assays of AML. Additionally, AIM2 demonstrates substantial prognostic value and holds promise as a prospective immunotherapeutic target for AML. Our findings indicate a significant correlation between AIM2 and immune infiltration in AML cases, potentially affecting the presence of neutrophils, macrophages, effector memory T cells (Tem), and monocytes. Furthermore, AIM2 is closely linked to various signaling pathways, such as immune cytokine release, immune antigen presentation, and inflammasome signaling, which could play a role in immune cell enrichment in AML.

Conclusions: Our study identified AMI2 as an ICM linked to FLT3 mutations. AMI2 may be involved in the activation of suppressive immune cell populations, such as macrophages, neutrophils, and monocytes. AIM2 could serve as a promising immunotherapeutic target for combination therapy with FLT3 inhibitors in AML.

FLT3突变相关免疫检查点分子在黑色素瘤2 (AIM2)中缺失有助于儿童和成人急性髓性白血病的免疫浸润:来自生物信息学分析的证据
背景:fms样酪氨酸激酶3 (FLT3)作为激酶抑制剂的一个关键靶点已经被证实,但其与免疫浸润的关系尚不清楚。本研究旨在探讨急性髓性白血病(AML)患者FLT3突变与免疫检查点分子(ICMs)之间的关系。方法:利用肿瘤基因组图谱(TCGA)和基因型-组织表达(GTEx)数据库鉴定与FLT3突变相关的ICMs。通过基因本体(GO)分析、京都基因与基因组百科全书(KEGG)分析和基因集富集分析(GSEA)分析与ICMs相关的信号通路。使用单样本GSEA (ssGSEA)、Cibersort和估计算法来评估AML中的免疫细胞浸润。结果:在FLT3突变的AML患者中,AIM2表达水平升高,对AML的进展和免疫抑制微环境的建立起重要作用。在AML离体检测中,AIM2的表达与临床相关药物的敏感性显著相关。此外,AIM2具有重要的预后价值,有望成为AML的潜在免疫治疗靶点。我们的研究结果表明,AML病例中AIM2与免疫浸润之间存在显著相关性,可能影响中性粒细胞、巨噬细胞、效应记忆T细胞(Tem)和单核细胞的存在。此外,AIM2与多种信号通路密切相关,如免疫细胞因子释放、免疫抗原呈递、炎性体信号传导等,可能在AML的免疫细胞富集中发挥作用。结论:我们的研究确定AMI2是与FLT3突变相关的ICM。AMI2可能参与抑制免疫细胞群的激活,如巨噬细胞、中性粒细胞和单核细胞。AIM2与FLT3抑制剂联合治疗AML可能是一个有前景的免疫治疗靶点。
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来源期刊
CiteScore
2.10
自引率
0.00%
发文量
252
期刊介绍: Translational Cancer Research (Transl Cancer Res TCR; Print ISSN: 2218-676X; Online ISSN 2219-6803; http://tcr.amegroups.com/) is an Open Access, peer-reviewed journal, indexed in Science Citation Index Expanded (SCIE). TCR publishes laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer; results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of cancer patients. The focus of TCR is original, peer-reviewed, science-based research that successfully advances clinical medicine toward the goal of improving patients'' quality of life. The editors and an international advisory group of scientists and clinician-scientists as well as other experts will hold TCR articles to the high-quality standards. We accept Original Articles as well as Review Articles, Editorials and Brief Articles.
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