Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.
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.
Davis
R Eric
RE
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ngo
Vu N
VN
Lenz
Georg
G
Tolar
Pavel
P
Young
Ryan M
RM
Romesser
Paul B
PB
Kohlhammer
Holger
H
Lamy
Laurence
L
Zhao
Hong
H
Yang
Yandan
Y
Xu
Weihong
W
Shaffer
Arthur L
AL
Wright
George
G
Xiao
Wenming
W
Powell
John
J
Jiang
Jian-Kang
JK
Thomas
Craig J
CJ
Rosenwald
Andreas
A
Ott
German
G
Muller-Hermelink
Hans Konrad
HK
Gascoyne
Randy D
RD
Connors
Joseph M
JM
Johnson
Nathalie A
NA
Rimsza
Lisa M
LM
Campo
Elias
E
Jaffe
Elaine S
ES
Wilson
Wyndham H
WH
Delabie
Jan
J
Smeland
Erlend B
EB
Fisher
Richard I
RI
Braziel
Rita M
RM
Tubbs
Raymond R
RR
Cook
J R
JR
Weisenburger
Dennis D
DD
Chan
Wing C
WC
Pierce
Susan K
SK
Staudt
Louis M
LM
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
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