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Nat Med. 2018 Jun;24(6):868-880. doi: 10.1038/s41591-018-0028-4. Epub 2018 May 21.

The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia.

Author information

1
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
2
Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain.
3
Departament de Fonaments Clinics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
4
Molecular Biology, NCMLS, FNWI, Radboud University, Nijmegen, The Netherlands.
5
Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain.
6
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
7
Structural Genomics Group, CNAG-CRG, The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
8
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
9
Nuclear Dynamics Program, Babraham Institute, Babraham Research Campus, Cambridge, UK.
10
Core Biología Molecular, CDB, Hospital Clínic, Barcelona, Spain.
11
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
12
Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology and UPF, Barcelona, Spain.
13
Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
14
Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain.
15
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
16
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK.
17
Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
18
Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain.
19
Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona, Spain.
20
Department of Biological Science, Florida State University, Tallahassee, FL, USA.
21
Max Planck Institut for Molecular Genetics, Berlin, Germany.
22
Institute of Human Genetics, University of Ulm and University Hospital of Ulm, Ulm, Germany.
23
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
24
Hematopathology Section, Hospital Clinic of Barcelona, Barcelona, Spain.
25
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. imartins@clinic.cat.
26
Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain. imartins@clinic.cat.
27
Departament de Fonaments Clinics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain. imartins@clinic.cat.

Abstract

Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.

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