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Researchers of the Blueprint Consortium decipher the
first epigenomes of chronic lymphocytic leukemia
Whole-genome DNA methylation analysis of 140 patients identifies the
cell of origin of the disease and discovers new molecular mechanisms
involved in its development.
The study published today in Nature Genetics presents a new perspective in cancer research as
it integrates the data from whole epigenome and genome sequencing of chronic lymphocytic
leukemia (CLL) patients. This research, directed by Iñaki Martin-Subero from Universidad de
Barcelona and IDIBAPS (Barcelona, Spain), represents the first collaborative effort between
two European high-impact research initiatives, such as the EU-funded Blueprint Consortium
and the CLL Genome Project funded by the Spanish government. These two initiatives are set
within the context of two world-wide Consortia, the International Human Epigenome
Consortium and the International Cancer Genome Consortium, respectively. In the study have
participated a total of 41 scientists from nine institutions associated with Blueprint Consortium
and/or the CLL Genome Project.
The Blueprint Consortium is supported by the 7th Framework Programme of the European
Union and aims at studying the epigenome of healthy and neoplastic blood cells
(www.blueprint-epigenome.eu). The project, which include the participation of 41 leading
European Institutions, is coordinated by Henk Stunnenberg from Radboud University in
Nijmegen (Netherlands) and represents the EU contribution to the International Human
Epigenome Consortium (www.ihec-epigenomes.net).
The Spanish Consortium for the study of the CLL Genome (www.cllgenome.es), funded by the
Spanish Government, is coordinated by Elias Campo (Hospital Clinic de Barcelona, IDIBAPS and
University of Barcelona, Spain) and Carlos López-Otín (University of Oviedo, Spain), and
includes the participation of more than a dozen Spanish institutions. This project belongs to an
international endeavor to sequence the cancer genome (www.icgc.org)
“In the previous research activities of Spanish CLL Genome Consortium we focused on the
analysis of mutated genes involved in the development of this disease. Now, thanks to our
work within the Blueprint Consortium, we have analyzed the full DNA methylome of CLL. This
approach has allowed us to identify the cells of origin of this kind of leukemia and to discover
new mechanisms that contribute to its development.”, says Elias Campo, co-coordinator of the
Spanish CLL Genome Project. During the last few years, Spanish CLL Genome Consortium has
published two outstanding works in Nature and Nature Genetics that characterized a
mutational genome map associated with this disease. “Our previous genetic studies identified
over 1000 genes mutated in the chronic lymphocytic leukemia, whereas this epigenomic
analysis has allowed us to detect over a million epigenetic changes in this disease. This
unexpected finding indicates that the epigenome of the cell suffers a massive shift during
leukemia development”, says Dr. Lopez-Otin, co-coordinator of the CLL Project.
Parallel study of the genome and epigenome is one of the new aspects of the Blueprint
researchers’ study. According to Dr Lopez-Otin, “genome is a source of information whereas
the role of epigenome is to execute this information so that the cells work properly”.
Therefore, epigenetics could be defined as a discipline that studies the molecular mechanisms
that allow gene activation or gene silencing. Thanks to the next-generation sequencing
technologies available in Centro Nacional de Analisis Genomico in Barcelona and the usage of
the high-density microarrays, this research has decoded for the first time the complete DNA
methylome of this disease and led to the unexpected discoveries. “Until now, most of the
epigenetic studies have been concentrated on the analysis of a limited fraction of the genome,
which was considered crucial for gene expression. Our results clearly show that the majority of
epigenetic alterations in CLL takes place in regions of the genome that were not examined in
previous studies”, explains Iñaki Martin-Subero. This study is announced only few weeks after
ENCODE Project publication, that has shown the majority of the regions in the genome
previously considered as “junk DNA” to contain the high number of sequences that regulate
gene activity. “When we compared our new data with those presented by ENCODE project, we
were surprised to discovered that the majority of the epigenetic alterations in leukemia targets
these newly described regulatory regions”, adds Martin-Subero.
This research article of the Blueprint and CLL Genome Consortia is an example of a successful
interdisciplinary biomedical investigation based on collaboration of specialists in epigenetics,
genetics, molecular biology, bioinformatics, anatomic pathology and clinical hematology. “This
integrative approach and team work are the key to success of the Consortium”, says Dr
Campo. One of the goals of Blueprint is to characterize the epigenomic alterations associated
with CLL and translate this knowledge to the benefit of patients in the clinic. The study
published today in Nature Genetics proposes a new approach to improve the diagnosis of this
leukemia. According to Dr Martin-Subero “we have discovered epigenetic patterns that allow
us to classify the chronic lymphocytic leukemia patients into three distinct groups with
different clinical outcome. Interestingly, each of these clinical groups maintains the epigenetic
imprint of its cell of origin. The leukemia subtypes with poor prognosis seem to derive from
naïve lymphocytes whereas the clinically favorable subtype is related to more mature
lymphocytes.”
Keys of the study
1. The next-generation sequencing technologies available in Centro Nacional de Análisis
Genómico (Barcelona, Spain) have allowed to characterize the leukemia epigenome in
a relatively short time.
2. The vast amount of data generated in this project has required new methodology
development and optimization, done principally by Martin-Subero team and
bioinformatics from Centro Nacional de Análisis Genómico of Barcelona.
3. The several decade work of Hospital Clinic in Barcelona in chronic lymphocytic
leukemia has provided the biological samples and clinical data of hundred of patients
that could be used to define the clinical impact of epigenetic study in this disease.
4. Apart from the analysis of epigenome of 139 chronic lymphocytic leukemia patients,
the researchers have analyzed several subtypes of normal lymphocytes from
peripheral blood that has allowed to identify the cell of origin of leukemia subtypes
with different clinic-biological features.
5. The integrative work of experts in different scientific and medical fields has not only
provided new insights into the molecular and cellular mechanisms underlying this
leukemia but also generated data that can improve the diagnosis of patients.
Countries involved in the Blueprint Consortium