Oncogenic CARD11 Mutations in Human Diffuse Large B Cell Lymphoma

doi:10.1126/science.1153629

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Science 319 (5870): 1676-1679

Oncogenic CARD11 Mutations in Human Diffuse Large B Cell Lymphoma

Georg Lenz,¹^* R. Eric Davis,¹^* 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,⁴^,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^,12 Richard I. Fisher,¹³^,14 Wing C. Chan,¹⁵ Louis M. Staudt¹

Abstract: Diffuse large B cell lymphoma (DLBCL) is the most common formof non-Hodgkin's lymphoma. In the least curable (ABC) subtypeof DLBCL, survival of the malignant cells is dependent on constitutiveactivation of the nuclear factor– ${kappa}$ B (NF- ${kappa}$ B) signaling pathway.In normal B cells, antigen receptor–induced NF- ${kappa}$ B activationrequires CARD11, a cytoplasmic scaffolding protein. To determinewhether CARD11 contributes to tumorigenesis, we sequenced theCARD11 gene in human DLBCL tumors. We detected missense mutationsin 7 of 73 ABC DLBCL biopsies (9.6%), all within exons encodingthe coiled-coil domain. Experimental introduction of CARD11coiled-coil domain mutants into lymphoma cell lines resultedin constitutive NF- ${kappa}$ B activation and enhanced NF- ${kappa}$ B activity uponantigen receptor stimulation. These results demonstrate thatCARD11 is a bona fide oncogenein DLBCL, providing a geneticrationale for the development of pharmacological inhibitorsof the CARD11 pathway for DLBCL therapy.

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 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.
¹² Centre for Cancer Biomedicine, Faculty Division, Norwegian Radium Hospital, University of Oslo, N-0310 Oslo, Norway.
¹³ Southwest Oncology Group, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106, USA.
¹⁴ James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.
¹⁵ Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: lstaudt{at}mail.nih.gov

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