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Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia

BACKGROUND: The clinical course of chronic lymphocytic leukemia (CLL) is highly variable; some patients follow an indolent course, but others progress to a more advanced stage. The mutational status of rearranged immunoglobulin heavy chain variable (IGVH) genes in CLL is a feature that is widely rec...

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Autores principales: Yepes, Sally, Torres, Maria Mercedes, López-Kleine, Liliana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659237/
https://www.ncbi.nlm.nih.gov/pubmed/26606983
http://dx.doi.org/10.1186/s12864-015-2189-6
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author Yepes, Sally
Torres, Maria Mercedes
López-Kleine, Liliana
author_facet Yepes, Sally
Torres, Maria Mercedes
López-Kleine, Liliana
author_sort Yepes, Sally
collection PubMed
description BACKGROUND: The clinical course of chronic lymphocytic leukemia (CLL) is highly variable; some patients follow an indolent course, but others progress to a more advanced stage. The mutational status of rearranged immunoglobulin heavy chain variable (IGVH) genes in CLL is a feature that is widely recognized for dividing patients into groups that are related to their prognoses. However, the regulatory programs associated with the IGVH statuses are poorly understood, and markers that can precisely predict survival outcomes have yet to be identified. METHODS: In this study, (i) we reconstructed gene regulatory networks in CLL by applying an information-theoretic approach to the expression profiles of 5 cohorts. (ii) We applied master regulator analysis (MRA) to these networks to identify transcription factors (TFs) that regulate an IGVH mutational status signature. The IGVH mutational status signature was developed by searching for differentially expressed genes between the IGVH mutational statuses in numerous CLL cohorts. (iii) To evaluate the biological implication of the inferred regulators, prognostic values were determined using time to treatment (TTT) and overall survival (OS) in two different cohorts. RESULTS: A robust IGVH expression signature was obtained, and various TFs emerged as regulators of the signature in most of the reconstructed networks. The TF targets expression profiles exhibited significant differences with respect to survival, which allowed the definition of a reduced profile with a high value for OS. TCF7 and its targets stood out for their roles in progression. CONCLUSION: TFs and their targets, which were obtained merely from inferred regulatory associations, have prognostic implications and reflect a regulatory context for prognosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2189-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-46592372015-11-26 Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia Yepes, Sally Torres, Maria Mercedes López-Kleine, Liliana BMC Genomics Research Article BACKGROUND: The clinical course of chronic lymphocytic leukemia (CLL) is highly variable; some patients follow an indolent course, but others progress to a more advanced stage. The mutational status of rearranged immunoglobulin heavy chain variable (IGVH) genes in CLL is a feature that is widely recognized for dividing patients into groups that are related to their prognoses. However, the regulatory programs associated with the IGVH statuses are poorly understood, and markers that can precisely predict survival outcomes have yet to be identified. METHODS: In this study, (i) we reconstructed gene regulatory networks in CLL by applying an information-theoretic approach to the expression profiles of 5 cohorts. (ii) We applied master regulator analysis (MRA) to these networks to identify transcription factors (TFs) that regulate an IGVH mutational status signature. The IGVH mutational status signature was developed by searching for differentially expressed genes between the IGVH mutational statuses in numerous CLL cohorts. (iii) To evaluate the biological implication of the inferred regulators, prognostic values were determined using time to treatment (TTT) and overall survival (OS) in two different cohorts. RESULTS: A robust IGVH expression signature was obtained, and various TFs emerged as regulators of the signature in most of the reconstructed networks. The TF targets expression profiles exhibited significant differences with respect to survival, which allowed the definition of a reduced profile with a high value for OS. TCF7 and its targets stood out for their roles in progression. CONCLUSION: TFs and their targets, which were obtained merely from inferred regulatory associations, have prognostic implications and reflect a regulatory context for prognosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2189-6) contains supplementary material, which is available to authorized users. BioMed Central 2015-11-25 /pmc/articles/PMC4659237/ /pubmed/26606983 http://dx.doi.org/10.1186/s12864-015-2189-6 Text en © Yepes et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Yepes, Sally
Torres, Maria Mercedes
López-Kleine, Liliana
Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia
title Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia
title_full Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia
title_fullStr Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia
title_full_unstemmed Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia
title_short Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia
title_sort regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659237/
https://www.ncbi.nlm.nih.gov/pubmed/26606983
http://dx.doi.org/10.1186/s12864-015-2189-6
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