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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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.
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Authors and Affiliations
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.
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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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DOI: https://doi.org/10.1038/nature11378
