title: Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia.
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.
authors.affiliation: Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain;
authors.forename: Pedro G
authors.initials: PG
authors.lastname: Ferreira
authors.forename: Pedro
authors.initials: P
authors.lastname: Jares
authors.forename: Daniel
authors.initials: D
authors.lastname: Rico
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.forename: Alejandra
authors.initials: A
authors.lastname: Martínez-Trillos
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.forename: Simone
authors.initials: S
authors.lastname: Ecker
authors.forename: Abel
authors.initials: A
authors.lastname: González-Pérez
authors.forename: David G
authors.initials: DG
authors.lastname: Knowles
authors.forename: Jean
authors.initials: J
authors.lastname: Monlong
authors.forename: Rory
authors.initials: R
authors.lastname: Johnson
authors.forename: Victor
authors.initials: V
authors.lastname: Quesada
authors.forename: Sarah
authors.initials: S
authors.lastname: Djebali
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papasaikas
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.forename: Cristina
authors.initials: C
authors.lastname: Royo
authors.forename: Maite
authors.initials: M
authors.lastname: Cazorla
authors.forename: Magda
authors.initials: M
authors.lastname: Pinyol
authors.forename: Guillem
authors.initials: G
authors.lastname: Clot
authors.forename: Marta
authors.initials: M
authors.lastname: Aymerich
authors.forename: Maria
authors.initials: M
authors.lastname: Rozman
authors.forename: Marta
authors.initials: M
authors.lastname: Kulis
authors.forename: David
authors.initials: D
authors.lastname: Tamborero
authors.forename: Anaïs
authors.initials: A
authors.lastname: Gouin
authors.forename: Julie
authors.initials: J
authors.lastname: Blanc
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Martin-Subero
authors.forename: Nuria
authors.initials: N
authors.lastname: López-Bigas
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigó
mesh_terms: D000368:Aged; D001402:B-Lymphocytes; D001483:Base Sequence; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007135:Immunoglobulin Variable Region; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012270:Ribosomes / Q000235:genetics; D017381:Spliceosomes / Q000235:genetics
chemical_list: D007135:Immunoglobulin Variable Region