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Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics

Nature volume 490, pages 116–120 (2012)Cite this article

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Abstract

Burkitt’s lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies1. The normal germinal centre B cell is the presumed cell of origin for both BL and diffuse large B-cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may use different oncogenic pathways2. BL is subdivided into a sporadic subtype that is diagnosed in developed countries, the Epstein–Barr-virus-associated endemic subtype, and an HIV-associated subtype, but it is unclear whether these subtypes use similar or divergent oncogenic mechanisms. Here we used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC, the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival phosphatidylinositol-3-OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signalling. In 38% of sporadic BL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.

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Figure 1: Recurrently mutated genes in aggressive lymphomas determined by RNA-seq.
Figure 2: TCF3 is essential for Burkitt lymphoma viability.
Figure 3: Tonic BCR signalling and PI(3) kinase activity in Burkitt’s lymphoma.
Figure 4: Oncogenic CCND3 mutations in Burkitt’s lymphoma.

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Accession codes

Primary accessions

Gene Expression Omnibus

Protein Data Bank

Sequence Read Archive

Data deposits

Gene expression profiling data have been submitted to GEO under accession number GSE35163, RNA-seq data has been deposited in NCBI Sequence Read Archive (SRA048058) and ChIP-seq data has been deposited in NCBI Sequence Read Archive (SRA052618).

Change history

  • 10 September 2012

    The descriptions for the Supplementary Information files were originally mixed up. This has now been corrected.

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, an NCI SPECS grant (UO1-CA 114778), by the Foundation for NIH, through a gift from the Richard A. Lauderbaugh Memorial Fund, and by Cancer Research UK. This study was conducted under the auspices of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). R.S. was supported by the Dr Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe). D.J.H. is a Kay Kendall Leukaemia Fund Intermediate research fellow. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://biowulf.nih.gov). We thank K. Meyer for help with the GEO submission, T. Ellenberger for the TCF3 crystal structure coordinates, B. Tran (Center for Cancer Research Sequencing Facility) and K. Hartman for DNA sequencing and K. Rajewsky for discussions. The DLBCL data set is part of the Cancer Genomics Characterization Initiative (CGCI), supported by NCI contract N01-C0-12400 (http://cgap.nci.nih.gov/cgci.html/) and was obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap. We thank the participants in the EMBLEM Study (http://emblem.cancer.gov/) in Uganda, the EMBLEM Study staff for collecting and processing the samples and data, and the Government of Uganda for allowing the study to be done and samples to be exported for research.

Author information

Author notes

  1. Roland Schmitz, Ryan M. Young, Michele Ceribelli, Sameer Jhavar and Wenming Xiao: These authors contributed equally to this work.

Authors and Affiliations

  1. Metabolism Branch Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA,

    Roland Schmitz, Ryan M. Young, Michele Ceribelli, Sameer Jhavar, Meili Zhang, Arthur L. Shaffer, Daniel J. Hodson, Eric Buras, Yandan Yang, Weihong Xu, Hong Zhao, Holger Kohlhammer, Wyndham Wilson, Thomas A. Waldmann & Louis M. Staudt

  2. Division of Computational Bioscience, Bioinformatics and Molecular Analysis Section, Center for Information Technology, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Wenming Xiao, Xuelu Liu & John Powell

  3. Biometric Research Branch, DCTD, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA,

    George Wright

  4. Department of Pathology, University of Würzburg, 97080 Würzburg, Germany,

    Andreas Rosenwald & Hans Konrad Müller-Hermelink

  5. Department of Pathology and Medical Biology, Groningen University Medical Center, University of Groningen, 9713 GZ Groningen, The Netherlands,

    Philip Kluin

  6. Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, 70376 Stuttgart, Germany,

    German Ott

  7. British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada,

    Randy D. Gascoyne & Joseph M. Connors

  8. Department of Pathology, University of Arizona, Tucson, 85724, Arizona, USA

    Lisa M. Rimsza

  9. Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain,

    Elias Campo

  10. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA,

    Elaine S. Jaffe & Stefania Pittaluga

  11. Pathology Clinic, Rikshospitalet University Hospital, 0372 Oslo, Norway,

    Jan Delabie

  12. Faculty Division of the Norwegian Radium Hospital, Institute for Cancer Research, Rikshospitalet University Hospital and Center for Cancer Biomedicine, University of Oslo, 0310 Oslo, Norway,

    Erlend B. Smeland

  13. St. Mary's Hospital Lacor, Gulu 256, Uganda,

    Martin D. Ogwang

  14. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Steven J. Reynolds

  15. James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester 14642, New York, USA,

    Richard I. Fisher

  16. Oregon Health and Science University, Portland, 97239, Oregon, USA

    Rita M. Braziel

  17. Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, 44195, Ohio, USA

    Raymond R. Tubbs & James R. Cook

  18. Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, 68198, Nebraska, USA

    Dennis D. Weisenburger & Wing C. Chan

  19. School of Cancer Sciences, Birmingham Cancer Research UK Centre, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK,

    Martin Rowe & Alan B. Rickinson

  20. Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, Infections and Immunoepidemiology Branch, National Cancer Institute, NIH, Rockville, 20852, Maryland, USA

    Sam M. Mbulaiteye

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  1. Roland Schmitz
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  2. Ryan M. Young
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  41. Louis M. Staudt
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Contributions

R.S., R.M.Y., M.C., S.J., M.Z., H.K., A.L.S. and D.J.H. designed and performed experiments. T.A.W. designed experiments. W.Xu Y.Y., E.B. and H.Z. performed experiments. W.Xi., G.W., X.L. and J.P. analysed data. A.R., P.K., H.K.M.-H., G.O., R.D.G., J.M.C., L.M.R., E.C., E.S.J., J.D., E.B.S., R.I.F., R.M.B., R.R.T., J.R.C., D.D.W., W.C.C., S.P., W.W., M.D.O., S.J.R., S.M.M., M.R. and A.B.R. supplied BL patient samples or lines, and reviewed pathological and clinical data. L.M.S. designed and supervised research and wrote the manuscript.

Corresponding author

Correspondence to Louis M. Staudt.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Figures 1-8, Supplementary Tables 9-10 (see separate files for Supplementary Tables 1-8 and 11) and additional references. (PDF 1796 kb)

Supplementary Table 1

This file contains pSNV from RNA-seq analysis in BL and DLBCL and FL. (XLS 1152 kb)

Supplementary Table 2

This file contains Sanger sequence verification of pSNVs in BL identified by RNA-seq. (XLS 159 kb)

Supplementary Table 3

This file contains Sanger sequencing analysis of Exon 16 of TCF3 (NM_001136139 - E47 isoform) and the coding sequence of ID3 (NM_002167) in 412 cases of various lymphoma subtypes. (XLS 78 kb)

Supplementary Table 4

This file contains results from RNA interference screen in BL. (XLS 4423 kb)

Supplementary Table 5

This file shows TCF3 ChIP-seq peaks present in both BL41 and Namalwa Burkitt lymphoma data sets. (XLS 2552 kb)

Supplementary Table 6

This file shows genomic regions differentially bound by WT and N551K TCF3. (XLS 103 kb)

Supplementary Table 7

This file contains Rapamycin gene signature. (XLS 59 kb)

Supplementary Table 8

This file contains Sanger sequencing analysis of Exon 5 of CCND3 (NM_001760) in 604 cases of various lymphoma subtypes and Sanger sequencing and gene copy number analysis of CDKN2A (NM_000077) in 317 cases of DLBCL and BL. (XLS 96 kb)

Supplementary Table 11

This file contains Primers used for Sanger sequencing, shRNA sequences and Primers used for qChIP. (XLS 109 kb)

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Schmitz, R., Young, R., Ceribelli, M. et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 490, 116–120 (2012). https://doi.org/10.1038/nature11378

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