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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
- Source :
- RNA Biol
- Publication Year :
- 2020
- Publisher :
- Taylor & Francis, 2020.
-
Abstract
- 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.
- Subjects :
- CD34
Biology
Dioxygenases
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Cell Line, Tumor
Proto-Oncogene Proteins
Humans
RNA, Antisense
Cell Self Renewal
Promoter Regions, Genetic
Molecular Biology
030304 developmental biology
Adaptor Proteins, Signal Transducing
0303 health sciences
Gene knockdown
Membrane Glycoproteins
Gene Expression Regulation, Leukemic
Cell Biology
Antisense RNA
DNA Demethylation
DNA-Binding Proteins
Haematopoiesis
Leukemia, Myeloid, Acute
DNA demethylation
030220 oncology & carcinogenesis
Cancer research
Neoplastic Stem Cells
RNA Interference
RNA, Long Noncoding
Interleukin-3 receptor
Stem cell
Guanylate Kinases
Research Paper
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- RNA Biol
- Accession number :
- edsair.doi.dedup.....89e77aab9a9ab3e48a8e393979df8182