Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.
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.
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
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