|Table of Contents|

Prognostic analysis of pyroptosis and molecular mechanism of GZMB in acute myeloid leukemia based on TCGA and GTEx database

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2023 18
Page:
3376-3383
Research Field:
Publishing date:

Info

Title:
Prognostic analysis of pyroptosis and molecular mechanism of GZMB in acute myeloid leukemia based on TCGA and GTEx database
Author(s):
DANG Qingxiu1; LI Yang2; GUO Yanting1; SHEN Yangling1; GU Weiying1
1.Department of Hematology,the Third Affiliated Hospital of Soochow University,the First People's Hospital of Changzhou,Jiangsu Changzhou 213003,China;2.The School of Medicine，Jiangsu University，Jiangsu Zhenjiang 212031,China.
Keywords:
acute myeloid leukemia; TCGA; GTEx; pyroptosis; GZMB
PACS:
R733.71
DOI:
10.3969/j.issn.1672-4992.2023.18.008
Abstract:
Objective:Bioinformatics analysis was used to screen differentially expressed genes (DEGs) in acute myeloid leukemia (AML) and further validation and analysis of their prognostic value were performed，in order to identify and validate novel targets for AML therapy.Methods:The expression data and clinical characteristics of AML and normal samples were downloaded from TCGA and GTEX database.R software was used to screen the DEGs in tumor tissues and healthy controls.The DEGs were identified by Cox regression analysis and prognostic analysis was carried out by Lasso analysis.Univariate and multivariate Cox regression were applied to analyze the correlation between risk model,clinical traits and prognosis of AML patients.Kaplan-Meier method was used to analyze the relationship between GZMB expression and survival rate in the prognosis model.AML patients were divided into high GZMB expression group and low GZMB expression group,and gene set enrichment analysis (GSEA) was performed.Western blot and ELISA were used to verify GZMB/Caspase-3/GSDME-mediated cell scorching in AML.Results:Forty-five DEGs were analyzed for prognosis,and 7 genes (BAK1,CASP3,GZMB,GPX4,NLRP2,GSDMB and GSDMA) were included in the risk model construction.Age,FAB subtypes,and risk score were significantly associated with the prognosis of AML patients.The overall survival rate of the group with high expression of GZMB was lower than that of the group with low (P＜0.05).GSEA enrichment analysis showed that GZMB was mainly involved in cytokine signaling pathway,natural killer cell,B cell and T cell immune regulation signaling pathway (P＜0.05,FDR≤25%).Western blot results showed the participation of pyroptosis mediated by GZMB/Caspase-3/GSDME in AML.Conclusion:The prognostic model of AML constructed by bioinformatic analyses with seven cell scorch-related genes may provide reference for the individualized treatment and evaluation of AML patients.The GZMB/Caspase-3/GSDME-mediated pyroptosis is involved in AML.

References:

［1］ ZWAAN CM,KOLB EA,REINHARDT D,et al.Collaborative efforts driving progress in pediatric acute myeloid leukemia ［J］.J Clin Oncol,2015,33(27):2949-2962.
［2］ SHI J,GAO W,SHAO F.Pyroptosis:Gasdermin-mediated programmed necrotic cell death ［J］.Trends Biochem Sci,2017,42(4):245-254.
［3］ LIU X,LIEBERMAN J.A mechanistic understanding of pyroptosis:The fiery death triggered by invasive infection ［J］.Adv Immunol,2017,135:81-117.
［4］ LIU X,ZHANG Z,RUAN J,et al.Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores ［J］.Nature,2016,535(7610):153-158.
［5］ DING J,WANG K,LIU W,et al.Pore-forming activity and structural autoinhibition of the gasdermin family ［J］.Nature,2016,535(7610):111-116.
［6］ STRATMANN S,VESTERLUND M,UMER HM,et al.Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children ［J］.Leukemia,2023,37(3):550-559.
［7］ LIU Y,FANG Y,CHEN X,et al.Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome ［J］.Sci Immunol,2020,5(43):eaax7969.
［8］ JIANG Y,YANG Y,HU Y,et al.Gasdermin D restricts anti-tumor immunity during PD-L1 checkpoint blockade ［J］.Cell Rep,2022,41(4):111553.
［9］ HU L,CHEN M,CHEN X,et al.Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate ［J］.Cell Death Dis,2020,11(4):281.
［10］ ROGERS C,FERNANDES-ALNEMRI T,MAYES L,et al.Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death ［J］.Nat Commun,2017,8:14128.
［11］ DU T,GAO Q,ZHAO Y,et al.Long non-coding RNA LINC02474 affects metastasis and apoptosis of colorectal cancer by inhibiting the expression of GZMB ［J］.Front Oncol,2021,11:651796.
［12］ WARD GA,MCGRAW KL,ABBAS-AGHABABAZADEH F,et al.Oxidized mitochondrial DNA released after inflammasome activation is a disease biomarker for myelodysplastic syndromes ［J］.Blood Adv,2021,5(8):2216-2228.
［13］ JOHNSON DC,TAABAZUING CY,OKONDO MC,et al.DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia ［J］.Nat Med,2018,24(8):1151-1156.
［14］ OAKES V,WANG W,HARRINGTON B,et al.Cyclin A/Cdk2 regulates Cdh1 and claspin during late S/G2 phase of the cell cycle ［J］.Cell Cycle,2014,13(20):3302-3311.
［15］ WANG WJ,CHEN D,JIANG MZ,et al.Downregulation of gasdermin D promotes gastric cancer proliferation by regulating cell cycle-related proteins ［J］.J Dig Dis,2018,19(2):74-83.
［16］ KANG R,ZENG L,ZHU S,et al.Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis ［J］.Cell Host Microbe,2018,24(1):97-108.e104.
［17］ ZHANG Z,ZHANG Y,XIA S,et al.Gasdermin E suppresses tumour growth by activating anti-tumour immunity ［J］.Nature,2020,579(7799):415-420.
［18］ LAROCK DL,JOHNSON AF,WILDE S,et al.Group A streptococcus induces GSDMA-dependent pyroptosis in keratinocytes ［J］.Nature,2022,605(7910):527-531.
［19］ WANG Y,WANG C,QIU J,et al.Targeting CD96 overcomes PD-1 blockade resistance by enhancing CD8+ TIL function in cervical cancer ［J］.J Immunother Cancer,2022,10(3):e003667.

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江苏省常州市十四五卫生领军人才工程资助项目（编号：KY20221336）；江苏省卫生健康委员会重点项目（编号：ZD2021043）
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