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Therapeutic Implications of Activation of the Host Gene (Dleu2) Promoter for miR-15a/16-1 in Chronic Lymphocytic Leukemia (CLL)

Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical pro-apoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibit...

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Autores principales: Kasar, S, Underbayev, C, Yuan, Y, Hanlon, M, Aly, S, Chang, V, Batish, M, Gavrilova, T, Badiane, F, Degheidy, H, Marti, G, Raveche, E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508006/
https://www.ncbi.nlm.nih.gov/pubmed/23995789
http://dx.doi.org/10.1038/onc.2013.291
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author Kasar, S
Underbayev, C
Yuan, Y
Hanlon, M
Aly, S
Chang, V
Batish, M
Gavrilova, T
Badiane, F
Degheidy, H
Marti, G
Raveche, E
author_facet Kasar, S
Underbayev, C
Yuan, Y
Hanlon, M
Aly, S
Chang, V
Batish, M
Gavrilova, T
Badiane, F
Degheidy, H
Marti, G
Raveche, E
author_sort Kasar, S
collection PubMed
description Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical pro-apoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibited by CLL cells. Similarly, in a de novo murine model of CLL, the NZB strain, germline-encoded regulation of the syntenic region resulted in decreased miR-15a/16-1. In this paper we have identified additional molecular mechanisms regulating miR-15a/16-1 levels and shown that the transcription factor BSAP (B cell Specific Activator Protein) directly interacts with Dleu2, the host gene containing the mir-15a/16-1 loci and via negative regulation of the Dleu2 promoter results in repression of mir-15a/16 expression. CLL patient B cell expression levels of BSAP were increased compared to control sources of B cells. With the use of siRNA mediated repression, the levels of BSAP were decreased in vitro in the NZB derived malignant B1 cell line, LNC, and in ex vivo CLL patient PBMC. BSAP knockdown led to an increase in the expression of miR-15a/16-1 and an increase in apoptosis and a cell cycle arrest in both the cell line and patient PBMC. Moreover, using Dleu2 promoter analysis by chromatin immunoprecipitation (ChIP) assay we have shown that BSAP directly interacts with the Dleu2 promoter. Derepression of the Dleu2 promoter via inhibition of histone deacetylation combined with BSAP knockdown increased miR-15a/16 expression and increased malignant B cell death. In summary, therapy targeting enhanced host gene Dleu2 transcription may augment CLL therapy.
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spelling pubmed-45080062015-07-20 Therapeutic Implications of Activation of the Host Gene (Dleu2) Promoter for miR-15a/16-1 in Chronic Lymphocytic Leukemia (CLL) Kasar, S Underbayev, C Yuan, Y Hanlon, M Aly, S Chang, V Batish, M Gavrilova, T Badiane, F Degheidy, H Marti, G Raveche, E Oncogene Article Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical pro-apoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibited by CLL cells. Similarly, in a de novo murine model of CLL, the NZB strain, germline-encoded regulation of the syntenic region resulted in decreased miR-15a/16-1. In this paper we have identified additional molecular mechanisms regulating miR-15a/16-1 levels and shown that the transcription factor BSAP (B cell Specific Activator Protein) directly interacts with Dleu2, the host gene containing the mir-15a/16-1 loci and via negative regulation of the Dleu2 promoter results in repression of mir-15a/16 expression. CLL patient B cell expression levels of BSAP were increased compared to control sources of B cells. With the use of siRNA mediated repression, the levels of BSAP were decreased in vitro in the NZB derived malignant B1 cell line, LNC, and in ex vivo CLL patient PBMC. BSAP knockdown led to an increase in the expression of miR-15a/16-1 and an increase in apoptosis and a cell cycle arrest in both the cell line and patient PBMC. Moreover, using Dleu2 promoter analysis by chromatin immunoprecipitation (ChIP) assay we have shown that BSAP directly interacts with the Dleu2 promoter. Derepression of the Dleu2 promoter via inhibition of histone deacetylation combined with BSAP knockdown increased miR-15a/16 expression and increased malignant B cell death. In summary, therapy targeting enhanced host gene Dleu2 transcription may augment CLL therapy. 2013-09-02 2014-06-19 /pmc/articles/PMC4508006/ /pubmed/23995789 http://dx.doi.org/10.1038/onc.2013.291 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Kasar, S
Underbayev, C
Yuan, Y
Hanlon, M
Aly, S
Chang, V
Batish, M
Gavrilova, T
Badiane, F
Degheidy, H
Marti, G
Raveche, E
Therapeutic Implications of Activation of the Host Gene (Dleu2) Promoter for miR-15a/16-1 in Chronic Lymphocytic Leukemia (CLL)
title Therapeutic Implications of Activation of the Host Gene (Dleu2) Promoter for miR-15a/16-1 in Chronic Lymphocytic Leukemia (CLL)
title_full Therapeutic Implications of Activation of the Host Gene (Dleu2) Promoter for miR-15a/16-1 in Chronic Lymphocytic Leukemia (CLL)
title_fullStr Therapeutic Implications of Activation of the Host Gene (Dleu2) Promoter for miR-15a/16-1 in Chronic Lymphocytic Leukemia (CLL)
title_full_unstemmed Therapeutic Implications of Activation of the Host Gene (Dleu2) Promoter for miR-15a/16-1 in Chronic Lymphocytic Leukemia (CLL)
title_short Therapeutic Implications of Activation of the Host Gene (Dleu2) Promoter for miR-15a/16-1 in Chronic Lymphocytic Leukemia (CLL)
title_sort therapeutic implications of activation of the host gene (dleu2) promoter for mir-15a/16-1 in chronic lymphocytic leukemia (cll)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508006/
https://www.ncbi.nlm.nih.gov/pubmed/23995789
http://dx.doi.org/10.1038/onc.2013.291
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