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MiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.

ABSTRACT: MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy.

SUBMITTER: Jiang X

PROVIDER: S-EPMC5477496 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.

Jiang Xi X Hu Chao C Arnovitz Stephen S Bugno Jason J Yu Miao M Zuo Zhixiang Z Chen Ping P Huang Hao H Ulrich Bryan B Gurbuxani Sandeep S Weng Hengyou H Strong Jennifer J Wang Yungui Y Li Yuanyuan Y Salat Justin J Li Shenglai S Elkahloun Abdel G AG Yang Yang Y Neilly Mary Beth MB Larson Richard A RA Le Beau Michelle M MM Herold Tobias T Bohlander Stefan K SK Liu Paul P PP Zhang Jiwang J Li Zejuan Z He Chuan C Jin Jie J Hong Seungpyo S Chen Jianjun J

Nature communications 20160426

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in ...[more]

PMID: 27116251

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Project description:BackgroundAcute Myeloid Leukaemia (AML) is a highly heterogeneous disease. Studies in adult AML have identified epigenetic changes, specifically DNA methylation, associated with leukaemia subtype, age of onset and patient survival which highlights this heterogeneity. However, only limited DNA methylation studies have elucidated any associations in paediatric AML.MethodsWe interrogated DNA methylation on a cohort of paediatric AML FAB subtype M5 patients using the Illumina HumanMethylation450 (HM450) BeadChip, identifying a number of target genes with p <0.01 and ?? >0.4 between leukaemic and matched remission (n?=?20 primary leukaemic, n?=?13 matched remission). Amongst those genes identified, we interrogate DLEU2 methylation using locus-specific SEQUENOM MassARRAY® EpiTYPER® and an increased validation cohort (n?=?28 primary leukaemic, n?=?14 matched remission, n?=?17 additional non-leukaemic and cell lines). Following methylation analysis, expression studies were undertaken utilising the same patient samples for singleplex TaqMan gene and miRNA assays and relative expression comparisons.ResultsWe identified differential DNA methylation at the DLEU2 locus, encompassing the tumour suppressor microRNA miR-15a/16-1 cluster. A number of HM450 probes spanning the DLEU2/Alt1 Transcriptional Start Site showed increased levels of methylation in leukaemia (average over all probes >60%) compared to disease-free haematopoietic cells and patient remission samples (<24%) (p?<?0.001). Interestingly, DLEU2 mRNA down-regulation in leukaemic patients (p?<?0.05) was independent of the embedded mature miR-15a/16-1 expression. To assess prognostic significance of DLEU2 DNA methylation, we stratified paediatric AML patients by their methylation status. A subset of patients recorded methylation values for DLEU2 akin to non-leukaemic specimens, specifically patients with sole trisomy 8 and/or chromosome 11 abnormalities. These patients also showed similar miR-15a/16-1 expression to non-leukaemic samples, and potential improved disease prognosis.ConclusionsThe DLEU2 locus and embedded miRNA cluster miR-15a/16-1 is commonly deleted in adult cancers and shown to induce leukaemogenesis, however in paediatric AML we found the region to be transcriptionally repressed. In combination, our data highlights the utility of interrogating DNA methylation and microRNA in combination with underlying genetic status to provide novel insights into AML biology.

Dataset Information

MiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.

Publications

miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.

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