期刊
LEUKEMIA
卷 31, 期 12, 页码 2543-2551出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2017.116
关键词
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资金
- National Natural Science Foundation of China [81372713, 81672497, 81570124, 81270606, 81402048, 81372714]
- Liaoning Provincial Natural Science Foundation of China [2014023010]
- Reformation Project in the Key Clinical Departments of Provincial Hospitals on Construction of Diagnosis and Treatment Capacity in Liaoning Province [LNCCC-A02-2015]
- Medical Research Council UK [MR/N012097/1]
- Cancer Research UK [A12011]
- Breast Cancer Now [2012MayPR070, 2012NovPhD016]
- MRC [MR/N012097/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1243234] Funding Source: researchfish
- Cancer Research UK [12011] Funding Source: researchfish
- Medical Research Council [MR/N012097/1] Funding Source: researchfish
Long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis, exemplified by the recent finding that lncRNA maternally expressed gene 3 (MEG3) inhibits tumor growth in a p53-dependent manner. Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults, and TP53 mutations or loss are frequently detected in patients with therapy-related AML or AML with complex karyotype. Here, we reveal that MEG3 is significantly downregulated in AML and suppresses leukemogenesis not only in a p53-dependent, but also a p53-independent manner. In addition, MEG3 is proven to be transcriptionally activated by Wilms' tumor 1 (WT1), dysregulation of which by epigenetic silencing or mutations is causally involved in AML. Therefore MEG3 is identified as a novel target of the WT1 molecule. Ten-eleven translocation-2 (TET2) mutations frequently occur in AML and significantly promote leukemogenesis of this disorder. In our study, TET2, acting as a cofactor of WT1, increases MEG3 expression. Taken together, our work demonstrates that TET2 dysregulated WT1-MEG3 axis significantly promotes AML leukemogenesis, paving a new avenue for diagnosis and treatment of AML patients.
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