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.
authors.affiliation: Metabolism Branch Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Young
authors.forename: Michele
authors.initials: M
authors.lastname: Ceribelli
authors.forename: Sameer
authors.initials: S
authors.lastname: Jhavar
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.forename: Meili
authors.initials: M
authors.lastname: Zhang
authors.forename: George
authors.initials: G
authors.lastname: Wright
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hodson
authors.forename: Eric
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authors.lastname: Buras
authors.forename: Xuelu
authors.initials: X
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Holger
authors.initials: H
authors.lastname: Kohlhammer
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Philip
authors.initials: P
authors.lastname: Kluin
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rimsza
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Erlend B
authors.initials: EB
authors.lastname: Smeland
authors.forename: Martin D
authors.initials: MD
authors.lastname: Ogwang
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Reynolds
authors.forename: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: Rita M
authors.initials: RM
authors.lastname: Braziel
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tubbs
authors.forename: James R
authors.initials: JR
authors.lastname: Cook
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Wyndham
authors.initials: W
authors.lastname: Wilson
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: Martin
authors.initials: M
authors.lastname: Rowe
authors.forename: Sam M
authors.initials: SM
authors.lastname: Mbulaiteye
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D016259:Genes, myc / Q000235:genetics; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034622:RNA Interference; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056743:Cyclin D3; D051361:Cyclin-Dependent Kinase 6; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D011947:Receptors, Antigen, B-Cell; C534696:CCND3 protein, human; C407909:TCF3 protein, human; C075640:ID3 protein, human; C495911:CDK6 protein, human