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 M. Rimsza, Elias Campo, Elaine S. Jaffe, Jan Delabie, Erlend B. Smeland, Richard I. FisherWing C. Chan, Louis M. Staudt

Research output: Contribution to journalArticlepeer-review

577 Scopus citations

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

ASJC Scopus subject areas

  • General

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