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.

Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

“…31,32 This spontaneous complex formation was correlated previously with constitutive, receptorindependent, NF-kB activation. Here, we analyzed the subcellular distribution of DDK-CARD11 proteins by immunofluorescence after transfection into HEK 293 cells.…”

“…The mechanism for NF-kB activation by CARD11 variants in the CARD and coiled-coil domain has been described. 29,31 For those cSCC variants within the C-terminal, membrane-associated GUK region that lead to enhanced NF-kB activity, a likely mechanism is a negative regulatory function in keeping with the importance of the SH3 and GUK domains for CARD11-mediated NF-kB signaling. 37 SH3 and GUK domains likely regulate activity by controlling subcellular localization and crucial proteineprotein interactions.…”

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

“…Subsequent studies showed that chromosomal rearrangements at the NFKB2 locus occur in a variety of human lymphomas (Rayet and Gelinas, 1999). Other changes to NF-kB family proteins in cancer tissues include the amplification and mutation of REL (c-Rel) in leukemia and lymphomas (Rayet and Gelinas, 1999;Starczynowski et al, 2007); mutations in the IKBA (IkBa) gene and hemizygous frameshift mutations in IKBE (IkBe) in Hodgkin's lymphoma (Cabannes et al, 1999;Scolnick and Halazonetis, 2000) (Emmerich et al, 2003); the amplification and overexpression of the IKBKE (IKKe) gene, a member of the IKK family, in breast cancer cell lines and patient-derived tumors (Boehm et al, 2007); and the mutation or amplification of TRAF2, TRAF3, CYLD, CIAP2, CD40, LTBR, TACI, NIK, CARD11 and other activators of the NF-kB signaling pathway in several cancer types (Campbell et al, 1998;Keats et al, 2007;Lenz et al, 2008). In our study, several NF-kB target genes (IL8, ZFP36, CXCL1 and IL12A) were downregulated in response to CHFR overexpression (Figure 1b).…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…NF-kappa B (NF-κB) or Rel proteins comprise a family of Protein Cell & tence of NF-κB in the nucleus, is shown in a wide variety of tumor types, such as lymphoma, liver cancer, lung cancer, breast cancer, etc (Mann et al, 2006;Qiao et al, 2006;Baby et al, 2007;Lenz et al, 2008). Besides, NF-κB is activated in response to tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation, and environmental stimuli that commonly contribute to carcinogenesis.…”