Oncogenic CARD11 mutations in human diffuse large B cell lymphoma

Georg Lenz, R. Eric Davis, Vu N. Ngo, Lloyd Lam, Thaddeus C. George, George W. Wright, Sandeep S. Dave, Hong Zhao, Weihong Xu, Andreas Rosenwald, German Ott, Hans Konrad Muller-Hermelink, Randy D. Gascoyne, Joseph M. Connors, Lisa Rimsza, Elias Campo, Elaine S. Jaffe, Jan Delabie, Erlend B. Smeland, Richard I. FisherWing C. Chan, Louis M. Staudt

Research output: Contribution to journalArticle

554 Citations (Scopus)

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-κB (NF-κB) signaling pathway. In normal B cells, antigen receptor-induced NF-κB 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-κB activation and enhanced NF-κB activity upon antigen receptor stimulation. These results demonstrate that CARD11 is a bona fide oncogene in DLBCL, providing a genetic rationale for the development of pharmacological inhibitors of the CARD11 pathway for DLBCL therapy.

Original languageEnglish (US)
Pages (from-to)1676-1679
Number of pages4
JournalScience
Volume319
Issue number5870
DOIs
StatePublished - Mar 21 2008
Externally publishedYes

Fingerprint

Lymphoma, Large B-Cell, Diffuse
Mutation
Lymphoma
B-Lymphocytes
B-Cell Antigen Receptors
Antigen Receptors
Missense Mutation
Cell- and Tissue-Based Therapy
Oncogenes
Non-Hodgkin's Lymphoma
Exons
Cell Survival
Carcinogenesis
Pharmacology
Biopsy
Cell Line
Genes
Neoplasms
Proteins

ASJC Scopus subject areas

  • General

Cite this

Lenz, G., Davis, R. E., Ngo, V. N., Lam, L., George, T. C., Wright, G. W., ... Staudt, L. M. (2008). Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science, 319(5870), 1676-1679. https://doi.org/10.1126/science.1153629

Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. / Lenz, Georg; Davis, R. Eric; Ngo, Vu N.; Lam, Lloyd; George, Thaddeus C.; Wright, George W.; Dave, Sandeep S.; Zhao, Hong; Xu, Weihong; Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D.; Connors, Joseph M.; Rimsza, Lisa; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Fisher, Richard I.; Chan, Wing C.; Staudt, Louis M.

In: Science, Vol. 319, No. 5870, 21.03.2008, p. 1676-1679.

Research output: Contribution to journalArticle

Lenz, G, Davis, RE, Ngo, VN, Lam, L, George, TC, Wright, GW, Dave, SS, Zhao, H, Xu, W, Rosenwald, A, Ott, G, Muller-Hermelink, HK, Gascoyne, RD, Connors, JM, Rimsza, L, Campo, E, Jaffe, ES, Delabie, J, Smeland, EB, Fisher, RI, Chan, WC & Staudt, LM 2008, 'Oncogenic CARD11 mutations in human diffuse large B cell lymphoma', Science, vol. 319, no. 5870, pp. 1676-1679. https://doi.org/10.1126/science.1153629
Lenz G, Davis RE, Ngo VN, Lam L, George TC, Wright GW et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008 Mar 21;319(5870):1676-1679. https://doi.org/10.1126/science.1153629
Lenz, Georg ; Davis, R. Eric ; Ngo, Vu N. ; Lam, Lloyd ; George, Thaddeus C. ; Wright, George W. ; Dave, Sandeep S. ; Zhao, Hong ; Xu, Weihong ; Rosenwald, Andreas ; Ott, German ; Muller-Hermelink, Hans Konrad ; Gascoyne, Randy D. ; Connors, Joseph M. ; Rimsza, Lisa ; Campo, Elias ; Jaffe, Elaine S. ; Delabie, Jan ; Smeland, Erlend B. ; Fisher, Richard I. ; Chan, Wing C. ; Staudt, Louis M. / Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. In: Science. 2008 ; Vol. 319, No. 5870. pp. 1676-1679.
@article{b6a38dbbf59a4072b6fc8ffb7414c981,
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-κB (NF-κB) signaling pathway. In normal B cells, antigen receptor-induced NF-κB 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-κB activation and enhanced NF-κB activity upon antigen receptor stimulation. These results demonstrate that CARD11 is a bona fide oncogene in DLBCL, providing a genetic rationale for the development of pharmacological inhibitors of the CARD11 pathway for DLBCL therapy.",
author = "Georg Lenz and Davis, {R. Eric} and Ngo, {Vu N.} and Lloyd Lam and George, {Thaddeus C.} and Wright, {George W.} and Dave, {Sandeep S.} and Hong Zhao and Weihong Xu and Andreas Rosenwald and German Ott and Muller-Hermelink, {Hans Konrad} and Gascoyne, {Randy D.} and Connors, {Joseph M.} and Lisa Rimsza and Elias Campo and Jaffe, {Elaine S.} and Jan Delabie and Smeland, {Erlend B.} and Fisher, {Richard I.} and Chan, {Wing C.} and Staudt, {Louis M.}",
year = "2008",
month = "3",
day = "21",
doi = "10.1126/science.1153629",
language = "English (US)",
volume = "319",
pages = "1676--1679",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "5870",

}

TY - JOUR

T1 - Oncogenic CARD11 mutations in human diffuse large B cell lymphoma

AU - Lenz, Georg

AU - Davis, R. Eric

AU - Ngo, Vu N.

AU - Lam, Lloyd

AU - George, Thaddeus C.

AU - Wright, George W.

AU - Dave, Sandeep S.

AU - Zhao, Hong

AU - Xu, Weihong

AU - Rosenwald, Andreas

AU - Ott, German

AU - Muller-Hermelink, Hans Konrad

AU - Gascoyne, Randy D.

AU - Connors, Joseph M.

AU - Rimsza, Lisa

AU - Campo, Elias

AU - Jaffe, Elaine S.

AU - Delabie, Jan

AU - Smeland, Erlend B.

AU - Fisher, Richard I.

AU - Chan, Wing C.

AU - Staudt, Louis M.

PY - 2008/3/21

Y1 - 2008/3/21

N2 - 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-κB (NF-κB) signaling pathway. In normal B cells, antigen receptor-induced NF-κB 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-κB activation and enhanced NF-κB activity upon antigen receptor stimulation. These results demonstrate that CARD11 is a bona fide oncogene in DLBCL, providing a genetic rationale for the development of pharmacological inhibitors of the CARD11 pathway for DLBCL therapy.

AB - 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-κB (NF-κB) signaling pathway. In normal B cells, antigen receptor-induced NF-κB 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-κB activation and enhanced NF-κB activity upon antigen receptor stimulation. These results demonstrate that CARD11 is a bona fide oncogene in DLBCL, providing a genetic rationale for the development of pharmacological inhibitors of the CARD11 pathway for DLBCL therapy.

UR - http://www.scopus.com/inward/record.url?scp=41149136296&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41149136296&partnerID=8YFLogxK

U2 - 10.1126/science.1153629

DO - 10.1126/science.1153629

M3 - Article

C2 - 18323416

AN - SCOPUS:41149136296

VL - 319

SP - 1676

EP - 1679

JO - Science

JF - Science

SN - 0036-8075

IS - 5870

ER -