Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.
Lenz G,
Davis RE,
Ngo VN,
Lam L,
George TC,
Wright GW,
Dave SS,
Zhao H,
Xu W,
Rosenwald A,
Ott G,
Muller-Hermelink HK,
Gascoyne RD,
Connors JM,
Rimsza LM,
Campo E,
Jaffe ES,
Delabie J,
Smeland EB,
Fisher RI,
Chan WC,
Staudt LM.
Metabolism Branch, Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
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.
PMID: 18323416 [PubMed - indexed for MEDLINE]