LncRNA MAGI2-AS3 inhibits the self-renewal of leukaemic stem cells by promoting TET2-dependent DNA demethylation of the LRIG1 promoter in acute myeloid leukaemia
单位：[a]Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,China华中科技大学同济医学院附属协和医院[b]Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in LiverCirrhosis & National Clinical Research Center for Digestive Diseases, Beijing, China临床科室国家中心肝病分中心首都医科大学附属北京友谊医院[c]Laboratory of Clinical Immunology, Wuhan No. 1 Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China[d]Institute of Hematology, Union Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, China华中科技大学同济医学院附属协和医院
The presence or absence of cytogenetic mutations is proposed to be responsible for the pathogenesis of acute myeloid leukaemia (AML). However, the current classification system is inadequate to elucidate the molecular heterogeneity of the disease, and therapy failures frequently occur. Leukaemia stem cells (LSCs) initiate and maintain the clonal hierarchy of AML and exhibit properties of self-renewal remaining recalcitrant to conventional chemotherapy. In this study, we identified a novel long non-coding RNA (lncRNA) MAGI2 antisense RNA 3 (MAGI2-AS3) in AML and investigated its functional role in regulating LSCs self-renewal. LSCs were identified by immunoprofiling of CD34(+) CD123(+) in AML patients' marrow. MAGI2-AS3 exhibited a poor expression level in LSCs than the normal human haematopoietic stem cells. Lentivirus-mediated upregulation of MAGI2-AS3 or leucine-rich repeats and Ig-like domains 1 (LRIG1) impaired LSCs self-renewal. MAGI2-AS3-overexpressed LSCs acquired the ability of self-renewal following lentivirus-mediated knockdown of LRIG1. Methylation-dependent inhibition of LRIG1 was evident in LSCs. MAGI2-AS3 was found to induce occupancy of TET2 at the LRIG1 promoter. Lentivirus-mediated downregulation of TET2 could impair MAGI2-AS3-mediated elevation of LRIG1 and neutralize the inhibitory effect of MAGI2-AS3 on LSCs self-renewal. In vivo analysis indicated an elevated overall survival of NOD/SCID mice injected with LSCs in the presence of MAGI2-AS3. Altogether, the key findings support the potential of lncRNA MAGI2-AS3 to serve as a novel candidate for the improvement of AML treatment.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81470348, 81502222]
第一作者单位：[a]Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,China
通讯作者：
通讯机构：[d]Institute of Hematology, Union Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, China[*1]Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
推荐引用方式(GB/T 7714)：
Lijuan Chen,Xu Fan,Jianhua Zhu,et al.LncRNA MAGI2-AS3 inhibits the self-renewal of leukaemic stem cells by promoting TET2-dependent DNA demethylation of the LRIG1 promoter in acute myeloid leukaemia[J].RNA BIOLOGY.2020,17(6):784-793.doi:10.1080/15476286.2020.1726637.
APA：
Lijuan Chen,Xu Fan,Jianhua Zhu,Xuexin Chen,Yiling Liu&Hao Zhou.(2020).LncRNA MAGI2-AS3 inhibits the self-renewal of leukaemic stem cells by promoting TET2-dependent DNA demethylation of the LRIG1 promoter in acute myeloid leukaemia.RNA BIOLOGY,17,(6)
MLA：
Lijuan Chen,et al."LncRNA MAGI2-AS3 inhibits the self-renewal of leukaemic stem cells by promoting TET2-dependent DNA demethylation of the LRIG1 promoter in acute myeloid leukaemia".RNA BIOLOGY 17..6(2020):784-793
