Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep R...

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Authors: Ferreira, Pedro G., González-Pérez, Abel, Knowles, David G., Monlong, Jean, Johnson, Rory, Djebali, Sarah, Papasaikas, Panagiotis, Tamborero Noguera, David, Gouin, Anaïs, López Bigas, Núria, Guigó Serra, Roderic
Format: article
Status:Published version
Publication Date:2014
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/23763
Online Access:http://hdl.handle.net/10230/23763
http://dx.doi.org/10.1101/gr.152132.112
Access Level:Open access
Keyword:Leucèmia limfocítica crònica
Genòmica
Genètica humana -- Variació
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spelling Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemiaFerreira, Pedro G.González-Pérez, AbelKnowles, David G.Monlong, JeanJohnson, RoryDjebali, SarahPapasaikas, PanagiotisTamborero Noguera, DavidGouin, AnaïsLópez Bigas, NúriaGuigó Serra, RodericLeucèmia limfocítica crònicaGenòmicaGenètica humana -- VariacióChronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes—most of which are not differentially expressed—exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences.This work was funded by the Spanish Ministry of Economy and Competitivity (MINECO) through the Instituto de Salud Carlos III (ISCIII), Red Tema´tica de Investigación del Cáncer (RTICC) and Instituto Nacional de Bioinforma´tica (INB) from ISCIII, and Consolider CSD2007-00050. C.L.-O. is an investigator of the Botín Foundation and E.C. of the ICREA-Academia program. N.L.-B., D.T., and A.G.-P. acknowledge funding from the Spanish Ministry of Science and Technology (grant number SAF2009-06954). S.E. is supported by a fellowship from La Caixa.Cold Spring Harbor Laboratory Press (CSHL Press)201520152014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/23763http://dx.doi.org/10.1101/gr.152132.112reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésGenome Research. 2014;24:212-26info:eu-repo/grantAgreement/ES/2PN/CSD2007-00050info:eu-repo/grantAgreement/ES/3PN/SAF2009-06954This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.http://creativecommons.org/licenses/by-nc/3.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/237632026-05-29T05:05:01Z
dc.title.none.fl_str_mv Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
title Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
spellingShingle Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
Ferreira, Pedro G.
Leucèmia limfocítica crònica
Genòmica
Genètica humana -- Variació
title_short Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
title_full Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
title_fullStr Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
title_full_unstemmed Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
title_sort Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
dc.creator.none.fl_str_mv Ferreira, Pedro G.
González-Pérez, Abel
Knowles, David G.
Monlong, Jean
Johnson, Rory
Djebali, Sarah
Papasaikas, Panagiotis
Tamborero Noguera, David
Gouin, Anaïs
López Bigas, Núria
Guigó Serra, Roderic
author Ferreira, Pedro G.
author_facet Ferreira, Pedro G.
González-Pérez, Abel
Knowles, David G.
Monlong, Jean
Johnson, Rory
Djebali, Sarah
Papasaikas, Panagiotis
Tamborero Noguera, David
Gouin, Anaïs
López Bigas, Núria
Guigó Serra, Roderic
author_role author
author2 González-Pérez, Abel
Knowles, David G.
Monlong, Jean
Johnson, Rory
Djebali, Sarah
Papasaikas, Panagiotis
Tamborero Noguera, David
Gouin, Anaïs
López Bigas, Núria
Guigó Serra, Roderic
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Leucèmia limfocítica crònica
Genòmica
Genètica humana -- Variació
topic Leucèmia limfocítica crònica
Genòmica
Genètica humana -- Variació
description Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes—most of which are not differentially expressed—exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences.
publishDate 2014
dc.date.none.fl_str_mv 2014
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/23763
http://dx.doi.org/10.1101/gr.152132.112
url http://hdl.handle.net/10230/23763
http://dx.doi.org/10.1101/gr.152132.112
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Genome Research. 2014;24:212-26
info:eu-repo/grantAgreement/ES/2PN/CSD2007-00050
info:eu-repo/grantAgreement/ES/3PN/SAF2009-06954
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/3.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press (CSHL Press)
publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press (CSHL Press)
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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