Integrative multi-omic analysis of NLRP3 inflammasome dysregulation and subtyping for personalized treatment in acute myeloid leukemia.

IF 2.8 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM
Hong Zhang, Linlin Yang, Yukexin Liu, Dongju Wang, Liming Shi, Changyu Tian
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Abstract

Acute myeloid leukemia (AML) is a devastating form of blood cancer characterized by uncontrolled growth and impaired maturation of myeloid precursor cells in the bone marrow. Despite advancements in treatment strategies, the prognosis for AML patients remains poor. The NLRP3 inflammasome, a multi-protein complex involved in innate immunity and inflammation, has been implicated in various diseases; however, its role in AML development and progression is not well understood. In this study, we analyzed genomic, bulk-, and single-cell transcriptomic data to assess the contribution of NLRP3 inflammasome genes to AML. Results suggested that 28 NLRP3 inflammasome genes with clinical implications were dysregulated in AML. Notably, we identified seven prognosis-related genes: CASP1, CPTP, MEFV, NFKB2, PANX1, PYCARD, and SIRT2. To further investigate the functional relevance of NLRP3 inflammasome genes, we developed an NLRP3 score (Nscore) based on the expression levels of these seven genes. We identified four dysregulated gene clusters that distinguished high- and low-Nscore groups, enabling the identification of two distinct AML subtypes, with subtype 2 exhibiting worse overall survival than subtype 1. Additionally, using a network-based approach, we identified 62 NLRP3 inflammasome-related genes and constructed a risk score model with COL2A1, ITGB2, and SRC genes, providing a comprehensive assessment of patient risk stratification. We revealed a positive correlation between the Nscore and macrophage M1, suggesting potential drug response mechanisms. Based on the identified AML subtypes and their distinct mutational landscapes, we predicted potential treatment options, with Paclitaxel, Afuresertib, and Mitoxantrone emerging as potential therapeutic agents for the AML subtypes.

急性髓性白血病患者NLRP3炎性小体失调及亚型分型的综合多组学分析
急性髓性白血病(AML)是一种破坏性的血癌形式,其特征是骨髓中髓前体细胞生长不受控制和成熟受损。尽管治疗策略取得了进步,但AML患者的预后仍然很差。NLRP3炎性小体是一种参与先天免疫和炎症的多蛋白复合物,与多种疾病有关;然而,其在AML发生和进展中的作用尚不清楚。在这项研究中,我们分析了基因组、大细胞和单细胞转录组学数据,以评估NLRP3炎性体基因对AML的贡献。结果提示有28个具有临床意义的NLRP3炎性小体基因在AML中表达异常。值得注意的是,我们确定了7个预后相关基因:CASP1、CPTP、MEFV、NFKB2、PANX1、PYCARD和SIRT2。为了进一步研究NLRP3炎性小体基因的功能相关性,我们基于这7个基因的表达水平建立了NLRP3评分(Nscore)。我们鉴定了四个失调的基因簇,区分高和低nscore组,从而鉴定出两种不同的AML亚型,其中亚型2比亚型1表现出更差的总生存率。此外,使用基于网络的方法,我们确定了62个NLRP3炎症小体相关基因,并构建了COL2A1、ITGB2和SRC基因的风险评分模型,提供了患者风险分层的综合评估。我们发现Nscore与巨噬细胞M1呈正相关,提示潜在的药物反应机制。基于已确定的AML亚型及其独特的突变景观,我们预测了潜在的治疗选择,紫杉醇、阿富瑞替布和米托蒽醌成为AML亚型的潜在治疗药物。
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
Discover. Oncology
Discover. Oncology Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
2.40
自引率
9.10%
发文量
122
审稿时长
5 weeks
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