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Published Online March 6, 2008
Science DOI: 10.1126/science.1153629

Reports

Submitted on November 30, 2007
Accepted on February 5, 2008

Oncogenic CARD11 Mutations in Human Diffuse Large B Cell Lymphoma

Georg Lenz 1{dagger}, R. Eric Davis 1{dagger}, Vu N. Ngo 1, Lloyd Lam 1, Thaddeus C. George 2, George W. Wright 3, Sandeep S. Dave 1, Hong Zhao 1, Weihong Xu 1, Andreas Rosenwald 4, German Ott 5, Hans Konrad Muller-Hermelink 4, Randy D. Gascoyne 6, Joseph M. Connors 6, Lisa M. Rimsza 7, Elias Campo 8, Elaine S. Jaffe 9, Jan Delabie 10, Erlend B. Smeland 11, Richard I. Fisher 12, Wing C. Chan 13, Louis M. Staudt 1*

1 Metabolism Branch, Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
2 Amnis Corporation, Seattle, WA 98121, USA.
3 Biometric Research Branch, Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
4 Department of Pathology, University of Würzburg, 97080 Würzburg, Germany.
5 Department of Pathology, University of Würzburg, 97080 Würzburg, Germany.; Department of Clinical Pathology, Robert-Bosch-Krankenhaus, 70376 Stuttgart, Germany.
6 British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada.
7 Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
8 Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain.
9 Laboratory of Pathology, Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
10 Department of Immunology, Rikshospitalet-Radiumhospitalet Medical Center, N-0310 Oslo, Norway.
11 Institute for Cancer Research, Rikshospitalet University Hospital, N-0310 Oslo, Norway.; Centre for Cancer Biomedicine, Faculty Division, Norwegian Radium Hospital, University of Oslo, N-0310 Oslo, Norway.
12 Southwest Oncology Group, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106, USA.; James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.
13 Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

* To whom correspondence should be addressed.
Louis M. Staudt , E-mail: lstaudt{at}mail.nih.gov

{dagger}These authors contributed equally to this work.

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 NF-{kappa}B signaling pathway. In normal B cells, antigen receptor–induced NF-{kappa}B 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-{kappa}B activation and enhanced NF-{kappa}B 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.


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