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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics
Nature, Volume 490, No. 7418, Year 2012
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Description
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. © 2012 Macmillan Publishers Limited. All rights reserved.
Authors & Co-Authors
Schmitz, Roland
Unknown Affiliation
Young, Ryan M.
Unknown Affiliation
Ceribelli, Michele
Unknown Affiliation
Jhavar, Sameer
Unknown Affiliation
Xiao, Wenming
Unknown Affiliation
Zhang, Meili
Unknown Affiliation
Wright, George
Unknown Affiliation
Shaffer, Arthur L.
Unknown Affiliation
Hodson, Daniel J.
Unknown Affiliation
Buras, Eric
Unknown Affiliation
Liu, Xuelu
Unknown Affiliation
Powell, John
Unknown Affiliation
Yang, Yandan
Unknown Affiliation
Xu, Weihong
Unknown Affiliation
Zhao, Hong
Unknown Affiliation
Kohlhammer, Holger
Unknown Affiliation
Rosenwald, Andreas R.
Unknown Affiliation
Kluin, Philip
Unknown Affiliation
Müller-Hermelink, Hans Konrad
Unknown Affiliation
Ott, German K.
Unknown Affiliation
Gascoyne, Randy D.
Unknown Affiliation
Connors, Joseph M.
Unknown Affiliation
Rimsza, Lisa
Unknown Affiliation
Campo, Elías
Unknown Affiliation
Jaffe, Elaine S.
Unknown Affiliation
Delabie, Jan
Unknown Affiliation
Smeland, Erlend B.
Unknown Affiliation
Ogwang, Martin David
Unknown Affiliation
Reynolds, Steven James
Unknown Affiliation
Fisher, Richard I.
Unknown Affiliation
Braziel, Rita M.
Unknown Affiliation
Tubbs, Raymond R.
Unknown Affiliation
Cook, James R.
Unknown Affiliation
Weisenburger, Dennis D.
Unknown Affiliation
Chan, John (Wing C)
Unknown Affiliation
Pittaluga, Stefania
Unknown Affiliation
Wilson, Wyndham
Unknown Affiliation
Waldmann, Thomas A.
Unknown Affiliation
Rowe, Martin
Unknown Affiliation
Mbulaiteye, Sam M.
Unknown Affiliation
Rickinson, Alan B.
Unknown Affiliation
Staudt, Louis M.
Unknown Affiliation
Statistics
Citations: 909
Authors: 42
Affiliations: 18
Identifiers
Doi:
10.1038/nature11378
ISSN:
00280836
e-ISSN:
14764687
Research Areas
Cancer
Genetics And Genomics
Infectious Diseases