@article{e4556b86ca344a4c93f07e2eb4249a42,
title = "Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics",
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 strategies. 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 pathways. 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.",
author = "Roland Schmitz and Young, {Ryan M.} and Michele Ceribelli and Sameer Jhavar and Wenming Xiao and Meili Zhang and George Wright and Shaffer, {Arthur L.} and Hodson, {Daniel J.} and Eric Buras and Xuelu Liu and John Powell and Yandan Yang and Weihong Xu and Hong Zhao and Holger Kohlhammer and Andreas Rosenwald and Philip Kluin and M{\"u}ller-Hermelink, {Hans Konrad} and German Ott and Gascoyne, {Randy D.} and Connors, {Joseph M.} and Rimsza, {Lisa M.} and Elias Campo and Jaffe, {Elaine S.} and Jan Delabie and Smeland, {Erlend B.} and Ogwang, {Martin D.} and Reynolds, {Steven J.} and Fisher, {Richard I.} and Braziel, {Rita M.} and Tubbs, {Raymond R.} and Cook, {James R.} and Weisenburger, {Dennis D.} and Chan, {Wing C.} and Stefania Pittaluga and Wyndham Wilson and Waldmann, {Thomas A.} and Martin Rowe and Mbulaiteye, {Sam M.} and Rickinson, {Alan B.} and Staudt, {Louis M.}",
note = "Funding Information: 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 underthe auspices of theLymphoma/Leukemia MolecularProfiling Project (LLMPP). R.S. was supported by the Dr Mildred Scheel Stiftung f{\"u}r 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 processingthesamples and data,andthe Government ofUgandaforallowingthe study to be done and samples to be exported for research.",
year = "2012",
month = oct,
day = "4",
doi = "10.1038/nature11378",
language = "English (US)",
volume = "490",
pages = "116--120",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
number = "7418",
}