Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia
- Pedro G. Ferreira1,
- Pedro Jares2,
- Daniel Rico3,
- Gonzalo Gómez-López3,
- Alejandra Martínez-Trillos2,
- Neus Villamor2,
- Simone Ecker3,
- Abel González-Pérez1,
- David G. Knowles1,
- Jean Monlong1,
- Rory Johnson1,
- Victor Quesada4,
- Anaïs Gouin1,
- Sarah Djebali1,
- Mónica López-Guerra2,
- Dolors Colomer2,
- Cristina Royo2,
- Maite Cazorla2,
- Magda Pinyol2,
- Guillem Clot2,
- Marta Aymerich2,
- Maria Rozman2,
- Marta Kulis2,
- David Tamborero1,
- Panagiotis Papasaikas1,
- Julie Blanc5,
- Marta Gut5,
- Ivo Gut5,
- Xose S. Puente4,
- David G. Pisano3,
- José Ignacio Martin-Subero6,
- Nuria López-Bigas1,
- Armando López-Guillermo2,
- Alfonso Valencia3,
- Carlos López-Otín4,
- Elías Campo2 and
- Roderic Guigo1,7
- 1 Universitat Pompeu Fabra;
- 2 Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer;
- 3 Spanish National Cancer Research Centre;
- 4 Universidad de Oviedo;
- 5 Centro Nacional de Análisis Genómico;
- 6 Universitat de Barcelona
- ↵* Corresponding author; email: roderic.guigo{at}crg.cat
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, 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.
- Received November 15, 2012.
- Accepted November 12, 2013.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
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/.
