RT Journal
A1 Ferreira, Pedro G.
A1 Jares, Pedro
A1 Rico, Daniel
A1 Gómez-López, Gonzalo
A1 Martínez-Trillos, Alejandra
A1 Villamor, Neus
A1 Ecker, Simone
A1 González-Pérez, Abel
A1 Knowles, David G.
A1 Monlong, Jean
A1 Johnson, Rory
A1 Quesada, Victor
A1 Gouin, Anaïs
A1 Djebali, Sarah
A1 López-Guerra, Mónica
A1 Colomer, Dolors
A1 Royo, Cristina
A1 Cazorla, Maite
A1 Pinyol, Magda
A1 Clot, Guillem
A1 Aymerich, Marta
A1 Rozman, Maria
A1 Kulis, Marta
A1 Tamborero, David
A1 Papasaikas, Panagiotis
A1 Blanc, Julie
A1 Gut, Marta
A1 Gut, Ivo
A1 Puente, Xose S.
A1 Pisano, David G.
A1 Martin-Subero, José Ignacio
A1 López-Bigas, Nuria
A1 López-Guillermo, Armando
A1 Valencia, Alfonso
A1 López-Otín, Carlos
A1 Campo, Elías
A1 Guigo, Roderic
T1 Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
JF Genome Research 
JO Genome Research 
YR 2013 
FD November 21 
DO 10.1101/gr.152132.112 
SP gr.152132.112 
UL http://genome.cshlp.org/content/early/2013/11/21/gr.152132.112.abstract 
AB 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, non-coding RNAs and pseudogenes. Transposable elements are globally de-repressed 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 downregulated 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.