Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.
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.
Lenz
Georg
G
Metabolism Branch, Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Davis
R Eric
RE
Ngo
Vu N
VN
Lam
Lloyd
L
George
Thaddeus C
TC
Wright
George W
GW
Dave
Sandeep S
SS
Zhao
Hong
H
Xu
Weihong
W
Rosenwald
Andreas
A
Ott
German
G
Muller-Hermelink
Hans Konrad
HK
Gascoyne
Randy D
RD
Connors
Joseph M
JM
Rimsza
Lisa M
LM
Campo
Elias
E
Jaffe
Elaine S
ES
Delabie
Jan
J
Smeland
Erlend B
EB
Fisher
Richard I
RI
Chan
Wing C
WC
Staudt
Louis M
LM
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
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