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Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways

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 mutati...

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Autores principales: 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, E W-F, Wang, X, Liu, Q, Yan, J, Jin, B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729340/
https://www.ncbi.nlm.nih.gov/pubmed/28400619
http://dx.doi.org/10.1038/leu.2017.116
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author 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, E W-F
Wang, X
Liu, Q
Yan, J
Jin, B
author_facet 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, E W-F
Wang, X
Liu, Q
Yan, J
Jin, B
author_sort Lyu, Y
collection PubMed
description 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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spelling pubmed-57293402017-12-15 Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways 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, E W-F Wang, X Liu, Q Yan, J Jin, B Leukemia Original Article 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. Nature Publishing Group 2017-12 2017-05-02 /pmc/articles/PMC5729340/ /pubmed/28400619 http://dx.doi.org/10.1038/leu.2017.116 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ 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/
spellingShingle Original Article
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, E W-F
Wang, X
Liu, Q
Yan, J
Jin, B
Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways
title Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways
title_full Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways
title_fullStr Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways
title_full_unstemmed Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways
title_short Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways
title_sort dysfunction of the wt1-meg3 signaling promotes aml leukemogenesis via p53-dependent and -independent pathways
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729340/
https://www.ncbi.nlm.nih.gov/pubmed/28400619
http://dx.doi.org/10.1038/leu.2017.116
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