title: Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.
abstract: A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-kappaB pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-kappaB, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-kappa, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.forename: Pavel
authors.initials: P
authors.lastname: Tolar
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Young
authors.forename: Paul B
authors.initials: PB
authors.lastname: Romesser
authors.forename: Holger
authors.initials: H
authors.lastname: Kohlhammer
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamy
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.forename: George
authors.initials: G
authors.lastname: Wright
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Jiang
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
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: Nathalie A
authors.initials: NA
authors.lastname: Johnson
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: Wyndham H
authors.initials: WH
authors.lastname: Wilson
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: Rita M
authors.initials: RM
authors.lastname: Braziel
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tubbs
authors.forename: J 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: Susan K
authors.initials: SK
authors.lastname: Pierce
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D020816:Amino Acid Motifs; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D051925:CD79 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011947:Receptors, Antigen, B-Cell / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; D051925:CD79 Antigens; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C426242:CARD11 protein, human; D006162:Guanylate Cyclase