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

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

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

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dc.contributor.author Ferreira, Pedro G.ca
dc.contributor.author González-Pérez, Abelca
dc.contributor.author Knowles, David G.ca
dc.contributor.author Monlong, Jeanca
dc.contributor.author Johnson, Roryca
dc.contributor.author Djebali, Sarahca
dc.contributor.author Papasaikas, Panagiotisca
dc.contributor.author Tamborero Noguera, Davidca
dc.contributor.author Gouin, Anaïsca
dc.contributor.author López Bigas, Núriaca
dc.contributor.author Guigó Serra, Rodericca
dc.date.accessioned 2015-06-08T08:50:06Z
dc.date.available 2015-06-08T08:50:06Z
dc.date.issued 2014ca
dc.description.abstract 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.en
dc.description.sponsorship 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.en
dc.format.mimetype application/pdfca
dc.identifier.citation Ferreira PG, Jares P, Rico D, Gómez-López G, Martínez-Trillos A, Villamor N et al. Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia. Genome Research. 2014;24:212-26. DOI: 10.1101/gr.152132.112ca
dc.identifier.doi http://dx.doi.org/10.1101/gr.152132.112
dc.identifier.issn 1088-9051ca
dc.identifier.uri http://hdl.handle.net/10230/23763
dc.language.iso engca
dc.publisher Cold Spring Harbor Laboratory Press (CSHL Press)ca
dc.relation.ispartof Genome Research. 2014;24:212-26
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/CSD2007-00050
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2009-06954
dc.rights This 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/.en
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by-nc/3.0/
dc.subject.other Leucèmia limfocítica crònicaca
dc.subject.other Genòmicaca
dc.subject.other Genètica humana -- Variacióca
dc.title Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemiaen
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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