06:13am Tuesday 15 October 2019

The first epigenomes of the chronic lymphocytic leukemia are deciphered

The research integrates the results of the complete sequencing of the genome and epigenome of patients with leukemia. Researchers identify the cells that cause the disease, discover new molecular mechanisms involved in its development and improve its diagnosis.

The research is part of the Chronic Lymphocytic Leukemia Genome Spanish Consortium, with the participation of researchers from the BLUEPRINT European Consortium for the study of the epigenome. During the past two years this consortium, which is part of the International Cancer Genome Consortium, has published two works in the journals Nature and Nature Genetics that allowed the characterization of the genetic map of mutations associated with the disease.

The study was presented by its coordinators, Elías Campo, from the Faculty of Medicine of the University of Barcelona and from the Hospital Clínic, and Carlos López-Otín, from the University of Oviedo, together with the research director, Iñaki Martín-Subero, from the Faculty of Medicine of the UB and from the Agusti Pi i Sunyer Biomedical Research Institute (IDIBAPS). The presentation event was presided by the Spain’s secretary of state for research, development and innovation, Carmen Vela.

Elías Campo remembered that the previous studies carried out by the consortium were centred on the analysis of the genome mutations involved in the disease development. “In this new research —he explains— we have widened our perspective into the epigenome study, what led us to identify the cells that cause leukemia and the new mechanisms responsible for the evolution of the disease”.




“If previous genetic studies identified more than 1000 mutated genes in the chronic lymphocytic leukemia, the epigenomic analysis has revealed more than one million epigenetic alterations in this disease. It is an unexpected finding which indicates that the cells epigenome suffers a massive reprogrammation in the cancer development process”, declared López-Otín.

One of the great innovations of the new study is that the investigators have simultaneously analyzed the genome and the epigenome. Epigenetics is defined as the science that studies the set of molecular mechanisms which activate or inactivate genes. According to López-Otín, “the genome is a repository of information while the epigenome is responsible for implementing the information to the proper functioning of cells”.

Thanks to the new techniques of massive sequencing of the National Centre of Genomic Analysis in Barcelona, located in the Barcelona Science Park, and to the use of high density microarrays, this study has deciphered the whole epigenome of the disease and concluded into some surprising findings. The research director, Iñaki Martín-Subero, comments: “Until now, the majority of studies related to epigenetics were centred on the analysis of a small fraction of the genome that was considered relevant for gene expression. Our findings clearly show that the majority of epigenetic alterations are produced in genomic areas which have never been studied before”.

This study was published a few weeks after the publication of the results of the ENCODE project, which indicate that most regions of the genome that were considered ‘junk DNA’ actually contain a large number of regulatory regions of the gene activity. “By integrating the new data with the ENCODE Project researchers noted that most of epigenetic alterations in leukemia occurred in these new domains regulating gene activity”, explains Martín-Subero.

This study of the Chronic Lymphocytic Leukemia Genome Spanish Consortium is an example of interdisciplinary biomedical research. Specialists in epigenetics, genetics, molecular biology, bioinformatics, clinical pathology and hematology have collaborated to make it possible. “This integrative approach and working together is a key to the success of this consortium”, remarks Elías Campo.

The main aim of the Chronic Lymphocytic Leukemia Genome Spanish Consortium is to generate a comprehensive catalogue of genomic alterations involved in the development and progression of the disease. This information will improve our ability to diagnose and categorize the patients and will promote the advance in new therapeutic approaches. As the doctor Martín-Subero observes, “We discovered the epigenetic patterns that allow us to classify chronic lymphocytic leukemia patients into three groups, each one with a different clinical course”.



Reference of the article

Marta Kulis, Simon Heath, Marina Bibikova, Ana C. Queirós, Alba Navarro, Guillem Clot, Alejandra Martínez-Trillos, Giancarlo Castellano, Isabelle Brun-Heath, Magda Pinyol, Sergio Barberán-Soler, Panagiotis Papasaikas, Pedro Jares, Sílvia Beà, Daniel Rico, Simone Ecker, Miriam Rubio, Romina Royo, Vincent Ho, Brandy Klotzle, Lluís Hernández, Laura Conde, Mónica López-Guerra, Dolors Colomer, Neus Villamor, Marta Aymerich, María Rozman, Mónica Bayes, Marta Gut, Josep L. Gelpí, Modesto Orozco, Jian-Bing Fan, Víctor Quesada, Xose S. Puente, David G. Pisano, Alfonso Valencia, Armando López-Guillermo, Ivo Gut, Carlos López-Otín, Elías Campo and José I. Martín-Subero. “Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia“. Nature Genetics, October 2012. DOI: 10.1038/ng.2443

Universitat de Barcelona

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