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The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia

Nature Medicine volume 24, pages 868–880 (2018)Cite this article

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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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Fig. 1: CLL reference epigenomes.
Fig. 2: Chromatin states and its transitions in CLL.
Fig. 3: CLL specific regulatory landscape.
Fig. 4: De novo chromatin activity and accessibility changes in an extended CLL cohort.
Fig. 5: B cell related chromatin activity and accessibility signatures in the extended CLL cohort.
Fig. 6: Somatic genetic alterations in relation to chromatin activity and accessibility.

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Acknowledgements

This work was funded by the European Union’s Seventh Framework Programme through the Blueprint Consortium (grant agreement 282510), the International Cancer Genome Consortium (Chronic Lymphocytic Leukemia Genome consortium to E.C. and C.L.-O.), the European Hematology Association (Non-Clinical Advanced Research Fellowship to J.I.M.-S.), the World Wide Cancer Research Foundation Grant No. 16-1285 (to J.I.M.-S.), the Spanish Ministerio de Economía y Competitividad (MINECO) Grant No. SAF2015-64885-R (to E.C.) and Grant No. PMP15/00007, part of Plan Nacional de I+D+I and co-financed by the ISCIII-Sub-Directorate General for Evaluation and the European Regional Development Fund (FEDER–“Una manera de hacer Europa”) (to E.C.), the Generalitat de Catalunya Suport Grups de Recerca AGAUR 2014-SGR-795 (to E.C.), the CERCA Programme/Generalitat de Catalunya and CIBERONC. R.B. was supported by fellowships from the EU (Marie Skłodowska-Curie Inter European Fellowship) and the Lady TATA Memorial Trust (International Award), N.R. by the Acció instrumental d’incorporació de científics i tecnòlegs PERIS 2016 from the Generalitat de Catalunya and M.Ku. by an AOI grant of the Spanish Association Against Cancer. E.C. is an Academia Researcher of the “Institució Catalana de Recerca i Estudis Avançats” (ICREA) of the Generalitat de Catalunya. This work was partially developed at the Centro Esther Koplowitz (CEK, Barcelona, Spain). We are indebted to the HCB-IDIBAPS Biobank-Tumor Bank and Hematopathology Collection for sample procurement.

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Authors and Affiliations

  1. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Renée Beekman, Núria Russiñol, Guillem Clot, Ana C. Queirós, Anna Enjuanes, David Martín-García, Sílvia Beà, Magda Pinyol, Elias Campo & Jose I. Martin-Subero

  2. Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Barcelona, Spain

    Renée Beekman, Guillem Clot, Anna Enjuanes, David Martín-García, Sílvia Beà, Magda Pinyol, Marta Aymerich, Xabier Agirre, Felipe Prosper, Tycho Baumann, Julio Delgado, Armando López-Guillermo, Xose S. Puente, Carlos López-Otín, Elias Campo & Jose I. Martin-Subero

  3. Departament de Fonaments Clinics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

    Vicente Chapaprieta, Roser Vilarrasa-Blasi, Núria Verdaguer-Dot, Martí Duran-Ferrer, Elias Campo & Jose I. Martin-Subero

  4. Molecular Biology, NCMLS, FNWI, Radboud University, Nijmegen, The Netherlands

    Joost H. A. Martens & Hendrik G. Stunnenberg

  5. Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain

    Marta Kulis & Elias Campo

  6. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    François Serra, Julie Blanc, Marta Gut, Angelika Merkel, Simon Heath, Marc A. Martí-Renom & Ivo Gut

  7. Structural Genomics Group, CNAG-CRG, The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

    François Serra & Marc A. Martí-Renom

  8. Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

    François Serra & Marc A. Martí-Renom

  9. Nuclear Dynamics Program, Babraham Institute, Babraham Research Campus, Cambridge, UK

    Biola M. Javierre, Steven W. Wingett & Peter Fraser

  10. Core Biología Molecular, CDB, Hospital Clínic, Barcelona, Spain

    Giancarlo Castellano

  11. CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

    Julie Blanc, Marta Gut, Angelika Merkel, Simon Heath & Ivo Gut

  12. Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology and UPF, Barcelona, Spain

    Anna Vlasova, Sebastian Ullrich, Emilio Palumbo & Roderic Guigó

  13. Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain

    Marta Aymerich

  14. Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain

    Romina Royo, Montserrat Puiggros & David Torrents

  15. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    David Torrents & Marc A. Martí-Renom

  16. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK

    Avik Datta, Ernesto Lowy, Myrto Kostadima, Maša Roller, Laura Clarke & Paul Flicek

  17. Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain

    Xabier Agirre & Felipe Prosper

  18. Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain

    Felipe Prosper

  19. Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona, Spain

    Tycho Baumann, Julio Delgado & Armando López-Guillermo

  20. Department of Biological Science, Florida State University, Tallahassee, FL, USA

    Peter Fraser

  21. Max Planck Institut for Molecular Genetics, Berlin, Germany

    Marie-Laure Yaspo

  22. Institute of Human Genetics, University of Ulm and University Hospital of Ulm, Ulm, Germany

    Reiner Siebert

  23. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain

    Xose S. Puente & Carlos López-Otín

  24. Hematopathology Section, Hospital Clinic of Barcelona, Barcelona, Spain

    Elias Campo

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Contributions

The Chronic Lymphocytic Leukemia Genome consortium and the BLUEPRINT consortium contributed to this study respectively as part of the International Cancer Genome Consortium and the International Human Epigenome Consortium. Investigator contributions were as follows: T.B., J.D., A.L.-G., D.M.-G., S.B., M.P., M.A., M.Ku., N.V.-D., X.A. and F.P. contributed to sample collection (CLL and normal B cells) as well as to their biological and clinical annotation. M.P., N.V.-D., M.G. and I.G. contributed to WGS data generation. N.R., N.V.-D., J.H.A.M., H.G.S., J.I.M.-S., M.G., I.G. and M.-L.Y. contributed to histone mark, ATAC-seq, methylome and transcriptome data generation. R.V.-B., J.B., M.G., I.G., J.I.M.-S., B.M.J., P.Fr., N.V.-D., A.E., A.C.Q. and R.B. contributed to in situ HiC, promoter capture HiC and 4C-seq data generation. X.S.P. and C.L.-O. contributed to WGS data analysis. R.B., V.C., J.H.A.M., M.D.-F., M.Ku., G.Cl., G.Ca., A.M., S.H., A.V., S.U., E.P., R.G., R.R., M.P., D.T., A.D., E.L., M.Ko., M.R., L.C., P.Fl. and J.I.M.-S. contributed to histone mark, ATAC-seq, methylome and transcriptome data analysis. R.V.-B., F.S., M.A.M.-R., S.W.W., B.M.J., P.Fr. and R.B. contributed to in situ HiC, promoter capture HiC and 4C-seq data analysis. C.L.-O., E.C., H.G.S. and R.S. participated in the study design and data interpretation together with R.B. and J.I.M.-S. R.B. and J.I.M.-S. directed the research and wrote the manuscript.

Corresponding author

Correspondence to Jose I. Martin-Subero.

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The authors declare no competing interests.

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Supplementary information

Supplementary Figures

Supplementary Figures 1-19

Reporting Summary

Supplementary Table 1

Patient characteristics

Supplementary Table 2

K-means clusters

Supplementary Table 3

Differential DNA methylation in CLL

Supplementary Table 4

Genes related to K-means clusters histone marks

Supplementary Table 5

Gene ontology terms

Supplementary Table 6

Chromatin states related to K-means clusters histone marks

Supplementary Table 7

De novo active and inactive regulatory elements in CLL

Supplementary Table 8

Enriched transcription factor motifs

Supplementary Table 9

Differentially active/accessible regions U-CLL and M-CLL

Supplementary Table 10

Overlap cell of origin signature DNA methylation and ATACseq

Supplementary Table 11

Patient groups somatic mutations and structural variants

Supplementary Table 12

Differential regions and target genes related to somatic genetic

Supplementary Table 13

Regions considered IG or SHM target loci in this study

Supplementary Table 14

Data quality measures

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Beekman, R., Chapaprieta, V., Russiñol, N. et al. The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia. Nat Med 24, 868–880 (2018). https://doi.org/10.1038/s41591-018-0028-4

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