Oncogenic CARD11 Mutations in Human Diffuse Large B Cell Lymphoma

G Lenz, RE Davis, VN Ngo, L Lam, TC George… - Science, 2008 - science.org
G Lenz, RE Davis, VN Ngo, L Lam, TC George, GW Wright, SS Dave, H Zhao, W Xu…
Science, 2008science.org
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 …
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.
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