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Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia
We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b e...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796978/ https://www.ncbi.nlm.nih.gov/pubmed/29435107 http://dx.doi.org/10.18632/oncotarget.23150 |
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author | Ngankeu, Apollinaire Ranganathan, Parvathi Havelange, Violaine Nicolet, Deedra Volinia, Stefano Powell, Bayard L. Kolitz, Jonathan E. Uy, Geoffrey L. Stone, Richard M. Kornblau, Steven M. Andreeff, Michael Croce, Carlo M. Bloomfield, Clara D. Garzon, Ramiro |
author_facet | Ngankeu, Apollinaire Ranganathan, Parvathi Havelange, Violaine Nicolet, Deedra Volinia, Stefano Powell, Bayard L. Kolitz, Jonathan E. Uy, Geoffrey L. Stone, Richard M. Kornblau, Steven M. Andreeff, Michael Croce, Carlo M. Bloomfield, Clara D. Garzon, Ramiro |
author_sort | Ngankeu, Apollinaire |
collection | PubMed |
description | We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b expression. Using Sanger sequencing, we identified a germline thymidine (T) base deletion within the miR-29b-1/miR-29a cluster precursor in 16% of AML patients. Remarkably we found a significant enrichment for the presence of the miR-29 polymorphism in core binding factor (CBF) newly diagnosed AML patients (n = 61/303; 20%) with respect to age, sex and race matched controls (n = 43/402:11%, P < 0.01). Mechanistically, this polymorphism affects the expression ratio of mature miR-29b and miR-29a by dampening the processing of miR-29a. RNA immunoprecipitation assays showed reduced DROSHA binding capacity to the polymorphism with respect to the controls. Finally, we showed that this polymorphism negatively impacts the ability of miR-29b-1/miR-29a cluster to target MCL-1 and CDK6, both known miR-29 targets. |
format | Online Article Text |
id | pubmed-5796978 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-57969782018-02-12 Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia Ngankeu, Apollinaire Ranganathan, Parvathi Havelange, Violaine Nicolet, Deedra Volinia, Stefano Powell, Bayard L. Kolitz, Jonathan E. Uy, Geoffrey L. Stone, Richard M. Kornblau, Steven M. Andreeff, Michael Croce, Carlo M. Bloomfield, Clara D. Garzon, Ramiro Oncotarget Research Paper We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b expression. Using Sanger sequencing, we identified a germline thymidine (T) base deletion within the miR-29b-1/miR-29a cluster precursor in 16% of AML patients. Remarkably we found a significant enrichment for the presence of the miR-29 polymorphism in core binding factor (CBF) newly diagnosed AML patients (n = 61/303; 20%) with respect to age, sex and race matched controls (n = 43/402:11%, P < 0.01). Mechanistically, this polymorphism affects the expression ratio of mature miR-29b and miR-29a by dampening the processing of miR-29a. RNA immunoprecipitation assays showed reduced DROSHA binding capacity to the polymorphism with respect to the controls. Finally, we showed that this polymorphism negatively impacts the ability of miR-29b-1/miR-29a cluster to target MCL-1 and CDK6, both known miR-29 targets. Impact Journals LLC 2017-12-12 /pmc/articles/PMC5796978/ /pubmed/29435107 http://dx.doi.org/10.18632/oncotarget.23150 Text en Copyright: © 2018 Ngankeu et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Ngankeu, Apollinaire Ranganathan, Parvathi Havelange, Violaine Nicolet, Deedra Volinia, Stefano Powell, Bayard L. Kolitz, Jonathan E. Uy, Geoffrey L. Stone, Richard M. Kornblau, Steven M. Andreeff, Michael Croce, Carlo M. Bloomfield, Clara D. Garzon, Ramiro Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia |
title | Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia |
title_full | Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia |
title_fullStr | Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia |
title_full_unstemmed | Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia |
title_short | Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia |
title_sort | discovery and functional implications of a mir-29b-1/mir-29a cluster polymorphism in acute myeloid leukemia |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796978/ https://www.ncbi.nlm.nih.gov/pubmed/29435107 http://dx.doi.org/10.18632/oncotarget.23150 |
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