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-kappaB (NF-kappaB) signaling pathway. In normal B cells, antigen receptor-induced NF-kappaB 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-kappaB activation and enhanced NF-kappaB 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.

• Authors: 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 Fisher, Wing C Chan, Louis M Staudt
• Journal: Science (New York, N.Y.) (Science) Vol. 319 Issue 5870 Pg. 1676-9 (Mar 21 2008) ISSN: 1095-9203 [Electronic] United States
• PMID: 18323416 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• NF-kappa B
• Receptors, Antigen, B-Cell
• I-kappa B Kinase
• CARD11 protein, human
• Guanylate Cyclase

Topics

• Amino Acid Sequence
• Apoptosis Regulatory Proteins (chemistry, genetics, metabolism)
• CARD Signaling Adaptor Proteins (chemistry, genetics, metabolism)
• Cell Line, Tumor
• Cytoplasm (metabolism)
• Guanylate Cyclase (chemistry, genetics, metabolism)
• Humans
• I-kappa B Kinase (metabolism)
• Jurkat Cells
• Lymphoma, Large B-Cell, Diffuse (genetics)
• Molecular Sequence Data
• Mutation, Missense
• NF-kappa B
• Oncogenes
• Protein Structure, Tertiary
• Receptors, Antigen, B-Cell (physiology)
• Sequence Analysis, DNA