title: Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.
abstract: Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. In the least curable (ABC) subtype of DLBCL, survival of the malignant cells is dependent on constitutive activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway. In normal B cells, antigen receptor-induced NF-kappaB activation requires CARD11, a cytoplasmic scaffolding protein. To determine whether CARD11 contributes to tumorigenesis, we sequenced the CARD11 gene in human DLBCL tumors. We detected missense mutations in 7 of 73 ABC DLBCL biopsies (9.6%), all within exons encoding the coiled-coil domain. Experimental introduction of CARD11 coiled-coil domain mutants into lymphoma cell lines resulted in constitutive NF-kappaB activation and enhanced NF-kappaB activity upon antigen receptor stimulation. These results demonstrate that CARD11 is a bona fide oncogenein DLBCL, providing a genetic rationale for the development of pharmacological inhibitors of the CARD11 pathway for DLBCL therapy.
authors.affiliation: Metabolism Branch, Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
authors.forename: Lloyd
authors.initials: L
authors.lastname: Lam
authors.forename: Thaddeus C
authors.initials: TC
authors.lastname: George
authors.forename: George W
authors.initials: GW
authors.lastname: Wright
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dave
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Muller-Hermelink
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: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D006162:Guanylate Cyclase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D019169:Jurkat Cells; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016328:NF-kappa B; D009857:Oncogenes; D017434:Protein Structure, Tertiary; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D017422:Sequence Analysis, DNA
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D051550:I-kappa B Kinase; C426242:CARD11 protein, human; D006162:Guanylate Cyclase