Oncogenic CARD11 Mutations in Human Diffuse Large B Cell Lymphoma

• Published in: Science (American Association for the Advancement of Science) Vol. 319; no. 5870; pp. 1676 - 1679
• Main Authors: 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 M, Campo, Elias, Jaffe, Elaine S, Delabie, Jan, Smeland, Erlend B, Fisher, Richard I, Chan, Wing C, Staudt, Louis M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 21.03.2008; The American Association for the Advancement of Science
• Subjects: Amino Acid Sequence; Apoptosis Regulatory Proteins - chemistry; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; B cell lymphoma; B lymphocytes; Biological and medical sciences; Biomedical research; Biopsies; CARD Signaling Adaptor Proteins - chemistry; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; Cell aggregates; Cell Line, Tumor; Cell lines; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Cytoplasm - metabolism; Fundamental and applied biological sciences. Psychology; Genetic mutation; Genetics; Guanylate Cyclase - chemistry; Guanylate Cyclase - genetics; Guanylate Cyclase - metabolism; Hematologic and hematopoietic diseases; Humans; I-kappa B Kinase - metabolism; Jurkat Cells; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Medical research; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Mutation, Missense; NF-kappa B; Oncogenes; Protein Structure, Tertiary; Proteins; Receptors, Antigen, B-Cell - physiology; Research facilities; Sequence Analysis, DNA; T lymphocytes; Tumors; Human; Lymphoproliferative syndrome; Diffuse large B cell lymphoma; Malignant hemopathy; B-Lymphocyte; Mutation; Onc gene; Carcinogenesis; Cancer
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1153629

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 oncogenein DLBCL, providing a genetic rationale for the development of pharmacological inhibitors of the CARD11 pathway for DLBCL therapy.