Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents+BCL2 inhibitor venetoclax

doi:10.1186/s13148-024-01658-2

科研成果详情

题名	Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents+BCL2 inhibitor venetoclax
作者	Li, Danyang 1; Yuan, Yigang 1; Meng, Chen1; Lin, Zihan 1; Zhao, Min 1; Shi, Liuzhi2; Li, Min 1; Ye, Daijiao1; Cai, Yue3; He, Xiaofei1,4; Ye, Haige5; Zhou, Shujuan5; Zhou, Haixia 4,6; Gao, Shenmeng1,4
发表日期	2024-03-26
发表期刊	Clinical Epigenetics 影响因子和分区
语种	英语
原始文献类型	Article
关键词	DNA hypermethylation Hypomethylation agents Acute lymphoblastic leukemia microRNA BCL2
其他关键词	CELL-PROLIFERATION ; TUMOR-SUPPRESSOR ; STEM-CELL ; APOPTOSIS ; TUMORIGENESIS ; CARCINOMA ; MIGRATION ; GENES ; AML
摘要	Background miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells have high miR-182 promoter methylation has not been determined.Methods To assess the methylation status of the miR-182 promoter, methylation and unmethylation-specific PCR analysis, bisulfite-sequencing analysis, and MethylTarget (TM) assays were performed to measure the frequency of methylation at the miR-182 promoter. Bone marrow cells were isolated from miR-182 knockout (182KO) and 182 wild type (182WT) mice to construct BCR-ABL (P190) and Notch-induced murine B-ALL and T-ALL models, respectively. Primary ALL samples were performed to investigate synergistic effects of the hypomethylation agents (HMAs) and the BCL2 inhibitor venetoclax (Ven) in vitro.Results miR-182 (miR-182-5P) expression was substantially lower in ALL blasts than in normal controls (NCs) because of DNA hypermethylation at the miR-182 promoter in ALL blasts but not in normal controls (NCs). Knockout of miR-182 (182KO) markedly accelerated ALL development, facilitated the infiltration, and shortened the OS in a BCR-ABL (P190)-induced murine B-ALL model. Furthermore, the 182KO ALL cell population was enriched with more leukemia-initiating cells (CD43+B220+ cells, LICs) and presented higher leukemogenic activity than the 182WT ALL population. Furthermore, depletion of miR-182 reduced the OS in a Notch-induced murine T-ALL model, suggesting that miR-182 knockout accelerates ALL development. Mechanistically, overexpression of miR-182 inhibited proliferation and induced apoptosis by directly targeting PBX3 and BCL2, two well-known oncogenes, that are key targets of miR-182. Most importantly, DAC in combination with Ven had synergistic effects on ALL cells with miR-182 promoter hypermethylation, but not on ALL cells with miR-182 promoter hypomethylation.Conclusions Collectively, we identified miR-182 as a tumor suppressor gene in ALL cells and low expression of miR-182 because of hypermethylation facilitates the malignant phenotype of ALL cells. DAC + Ven cotreatment might has been applied in the clinical try for ALL patients with miR-182 promoter hypermethylation. Furthermore, the methylation frequency at the miR-182 promoter should be a potential biomarker for DAC + Ven treatment in ALL patients.
资助项目	National Natural Science Foundation of China
出版者	BMC
ISSN	1868-7075
EISSN	1868-7083
卷号	16 期号:1
DOI	10.1186/s13148-024-01658-2
页数	17
WOS类目	Oncology ; Genetics & Heredity
WOS研究方向	Oncology ; Genetics & Heredity
WOS记录号	WOS:001190945300001
收录类别	SCIE ; SCOPUS
URL	查看原文
PubMed ID	38528641
SCOPUSEID	2-s2.0-85188527424
通讯作者地址	[Gao, Shenmeng]Medical Research Center,The First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,325000,China ; [Zhou, Haixia]The Key Laboratory of Pediatric Hematology and Oncology Diseases of Wenzhou,The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,109 Xuanyuanxi Road, Zhejiang Province,Wenzhou,China
Scopus学科分类	Molecular Biology;Genetics;Developmental Biology;Genetics (clinical)
SCOPUS_ID	SCOPUS_ID:85188527424
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/210999
专题	附属第一医院第一临床医学院（信息与工程学院）、附属第一医院附属第二医院第二临床医学院、附属第二医院、育英儿童医院第一临床医学院（信息与工程学院）、附属第一医院_临床检验诊断学
通讯作者	Zhou, Haixia; Gao, Shenmeng
作者单位	1.Medical Research Center,The First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,325000,China; 2.Department of Clinical Laboratory,The First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,China; 3.Department of Clinical Medicine,Wenzhou Medical University,Chashan District, Zhejiang Province,Wenzhou,China; 4.The Key Laboratory of Pediatric Hematology and Oncology Diseases of Wenzhou,The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,109 Xuanyuanxi Road, Zhejiang Province,Wenzhou,China; 5.Department of Hematology,The First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,China; 6.Department of Hematology,The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,109 Xuanyuanxi Road, Zhejiang Province,Wenzhou,China
第一作者单位	附属第一医院; 第一临床医学院（信息与工程学院）、附属第一医院
通讯作者单位	附属第一医院; 第一临床医学院（信息与工程学院）、附属第一医院; 第二临床医学院，附属第二医院、育英儿童医院; 附属第二医院
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Li, Danyang,Yuan, Yigang,Meng, Chen,et al. Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents+BCL2 inhibitor venetoclax[J]. Clinical Epigenetics,2024,16(1).
APA	Li, Danyang., Yuan, Yigang., Meng, Chen., Lin, Zihan., Zhao, Min., ... & Gao, Shenmeng. (2024). Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents+BCL2 inhibitor venetoclax. Clinical Epigenetics, 16(1).
MLA	Li, Danyang,et al."Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents+BCL2 inhibitor venetoclax".Clinical Epigenetics 16.1(2024).