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Dysfunction of the WT1-MEG3 Signaling Promotes AML Leukemogenesis via p53 Dependent and Independent Pathways

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Title: Dysfunction of the WT1-MEG3 Signaling Promotes AML Leukemogenesis via p53 Dependent and Independent Pathways
Authors: Lyu, Y
Lou, J
Yang, Y
Feng, J
Hao, Y
Huang, S
Yin, L
Xu, J
Huang, D
Ma, B
Zou, D
Wang, Y
Zhang, Y
Zhang, B
Chen, P
Yu, K
Lam, EW
Wang, X
Liu, Q
Yan, J
Jin, B
Item Type: Journal Article
Abstract: 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.
Issue Date: 2-May-2017
Date of Acceptance: 4-Apr-2017
URI: http://hdl.handle.net/10044/1/46265
DOI: https://dx.doi.org/10.1038/leu.2017.116
ISSN: 1476-5551
Publisher: Nature Publishing Group
Start Page: 2543
End Page: 2551
Journal / Book Title: Leukemia
Volume: 31
Copyright Statement: © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article ’ s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/ by/4.0/
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Funder's Grant Number: C37/A12011
2012MayPR070
2014NovPhD326
Keywords: 1103 Clinical Sciences
1112 Oncology And Carcinogenesis
Immunology
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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