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miR-138-5p/RPS6KA1-AP2M1的失调与急性髓系白血病的不良预后相关。

Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML.

作者信息

Yu Dong-Hu, Chen Chen, Liu Xiao-Ping, Yao Jie, Li Sheng, Ruan Xiao-Lan

机构信息

Department of Biological Repositories, Human Genetics Resource Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China.

The Second Clinical College, Wuhan University, Wuhan, China.

出版信息

Front Cell Dev Biol. 2021 Feb 26;9:641629. doi: 10.3389/fcell.2021.641629. eCollection 2021.

DOI:10.3389/fcell.2021.641629
PMID:33732707
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7959750/
Abstract

Acute myeloid leukemia (AML) is a malignant disease of hematopoietic stem/progenitor cells, and most AML patients are in a severe state. Internal tandem duplication mutations in FLT3 gene (FLT3-ITD) detected in AML stem cells account for 20-30 percent of AML patients. In this study, we attempted to study the impact of the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis in AML, and the possible mechanisms caused by the impact by bioinformatics. Gene set variation analysis (GSVA) revealed that the PI3K-Akt-mTOR pathway positively correlated with the status of FLT3-ITD mutation. Multiple survival analyses were performed on TCGA-AML to screen the prognostic-related genes, and RPS6KA1 and AP2M1 are powerful prognostic candidates for overall survival in AML. WGCNA, KEGG/GO analysis, and the functional roles of RPS6KA1 and AP2M1 in AML were clarified by correlation analysis. We found that the expression levels of RPS6KA1 and AP2M1 were significantly associated with chemoresistance of AML, and the CXCL12/CXCR4 axis would regulate RPS6KA1/AP2M1 expression. Besides, miR-138-5p, regulated by the CXCL12/CXCR4 axis, was the common miRNA target of RPS6KA1 and AP2M1. Taken together, the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis activated the PI3K-Akt-mTOR pathway, and the increased expression of RPS6KA1 and AP2M1 caused by hsa-miR-138-5p downregulation regulates the multi-resistance gene expression leading to drug indications.

摘要

急性髓系白血病（AML）是一种造血干/祖细胞的恶性疾病，大多数AML患者病情严重。在AML干细胞中检测到的FLT3基因内部串联重复突变（FLT3-ITD）占AML患者的20%-30%。在本研究中，我们试图通过生物信息学研究FLT3-ITD突变与CXCL12/CXCR4轴相互作用对AML的影响以及该影响所导致的可能机制。基因集变异分析（GSVA）显示PI3K-Akt-mTOR通路与FLT3-ITD突变状态呈正相关。对TCGA-AML进行了多项生存分析以筛选预后相关基因，RPS6KA1和AP2M1是AML总生存的有力预后候选基因。通过相关性分析阐明了加权基因共表达网络分析（WGCNA）、KEGG/GO分析以及RPS6KA1和AP2M1在AML中的功能作用。我们发现RPS6KA1和AP2M1的表达水平与AML的化疗耐药性显著相关，且CXCL12/CXCR4轴会调节RPS6KA1/AP2M1的表达。此外，受CXCL12/CXCR4轴调控的miR-138-5p是RPS6KA1和AP2M1共同的miRNA靶点。综上所述，FLT3-ITD突变与CXCL12/CXCR4轴的相互作用激活了PI3K-Akt-mTOR通路，由hsa-miR-138-5p下调导致的RPS6KA1和AP2M1表达增加调节多耐药基因表达从而导致药物耐药。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/f2f0240d9cdd/fcell-09-641629-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/7ed5b9686791/fcell-09-641629-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/f9eacd0775f9/fcell-09-641629-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/0900b7bfb7a3/fcell-09-641629-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/e1655c0b3d0e/fcell-09-641629-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/c7f5d6e53c74/fcell-09-641629-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/f2f0240d9cdd/fcell-09-641629-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/7ed5b9686791/fcell-09-641629-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/66ca55f909e4/fcell-09-641629-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/bff382148232/fcell-09-641629-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/cc0ebb1fdb11/fcell-09-641629-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/f9eacd0775f9/fcell-09-641629-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/0900b7bfb7a3/fcell-09-641629-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/e1655c0b3d0e/fcell-09-641629-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/c7f5d6e53c74/fcell-09-641629-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce27/7959750/f2f0240d9cdd/fcell-09-641629-g009.jpg

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