FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas.
ABSTRACT BCL6 is the product of a proto-oncogene implicated in the pathogenesis of human B-cell lymphomas. By binding specific DNA sequences, BCL6 controls the transcription of a variety of genes involved in B-cell development, differentiation and activation. BCL6 is overexpressed in the majority of patients with aggressive diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adulthood, and transgenic mice constitutively expressing BCL6 in B cells develop DLBCLs similar to the human disease. In many DLBCL patients, BCL6 overexpression is achieved through translocation (~40%) or hypermutation of its promoter (~15%). However, many other DLBCLs overexpress BCL6 through an unknown mechanism. Here we show that BCL6 is targeted for ubiquitylation and proteasomal degradation by a SKP1–CUL1–F-box protein (SCF) ubiquitin ligase complex that contains the orphan F-box protein FBXO11 (refs 5, 6). The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Notably, tumour-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation. Reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death. FBXO11-deleted DLBCL cells generated tumours in immunodeficient mice, and the tumorigenicity was suppressed by FBXO11 reconstitution. We reveal a molecular mechanism controlling BCL6 stability and propose that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization. The deletions/mutations found in DLBCLs are largely monoallelic, indicating that FBXO11 is a haplo-insufficient tumour suppressor gene.
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ABSTRACT: Zinc is an essential micronutrient playing fundamental roles in cellular metabolism. It acts mostly through binding a wide range of proteins, thus affecting a broad spectrum of biological processes, which include cell division, growth and differentiation. Full annotation of zinc-binding proteins showed them to represent about 10 % of the human proteome, with over 300 enzymes containing zinc ions within their catalytic domains. Also, hundreds of key regulatory proteins, including transcription factors, require zinc for their activity. In this study, the whole set of zinc-binding proteins together with their direct interactors was listed and defined as the zinc proteome (ZNP). We interrogated pathway analysis tools to identify the cellular processes that are predicted to be affected by zinc availability. Network and functional enrichment analyses highlighted biological processes potentially affected by deregulated zinc homeostasis. This computational approach was also tested on a real case study: The possible involvement of ZNP network proteins in Crohn's disease pathogenesis was assessed on genes transcriptionally regulated in the intestine of patients affected by this condition. The analysis produced a network of pathways likely to be influenced by zinc and associated with Crohn's disease. These results highlight a central role for zinc in the tissue remodeling process which occurs upon gut inflammation, pointing at novel disease pathways whose effect could be worsened by zinc dyshomeostasis and impaired zinc fluxes in specific damaged areas. Overall, our computational approach could provide novel insights into pathological conditions and could therefore be used to drive mechanistic research in under-investigated fields of research. An interactive version of the determined ZNP network is available at URL http://126.96.36.199/ZNnetwork/ .Genes & Nutrition 11/2014; 9(6):436. DOI:10.1007/s12263-014-0436-0 · 3.42 Impact Factor
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ABSTRACT: Burkitt lymphoma (BL) is the most frequent B-cell lymphoma in childhood. Genetically, it is characterized by the presence of an IG-MYC translocation which is supposed to be an initiating but not sufficient event in Burkitt lymphomagenesis. In a recent whole-genome sequencing study of four cases, we showed that the gene encoding the ras homolog family member A (RHOA) is recurrently mutated in pediatric BL. Here, we analyzed RHOA by Sanger sequencing in a cohort of 101 pediatric B-cell lymphoma patients treated according to Non-Hodgkin's Lymphoma Berlin–Frankfurt–Münster (NHL-BFM) study protocols. Among the 78 BLs in this series, an additional five had RHOA mutations resulting in a total incidence of 7/82 (8.5%) with c.14G>A (p.R5Q) being present in three cases. Modeling the mutational effect suggests that most of them inactivate the RHOA protein. Thus, deregulation of RHOA by mutation is a recurrent event in Burkitt lymphomagenesis in children. © 2014 Wiley Periodicals, Inc.Genes Chromosomes and Cancer 11/2014; 53(11). DOI:10.1002/gcc.22202 · 3.84 Impact Factor
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ABSTRACT: The B-aggressive lymphoma-1 protein and ADP-ribosyltransferase BAL1/ARTD9 has been recently identified as a novel risk-related gene product in aggressive diffuse large B-cell lymphoma (DLBCL). BAL1 is constitutively expressed in a subset of high-risk DLBCL with an active host inflammatory response and suggested to be associated with interferon related gene expression. Here we identify BAL1 as a novel oncogenic survival factor in DLBCL and show that constitutive overexpression of BAL1 in DLBCL tightly associates with intrinsic interferon-gamma (IFNγ) signaling and constitutive activity of signal transducer and activator of transcription (STAT)-1. Remarkably, BAL1 stimulates the phosphorylation of both STAT1 isoforms STAT1α and STAT1β, on Y701 and thereby promoting the nuclear accumulation of the antagonistically acting and transcriptionally repressive isoform STAT1β. Moreover, BAL1 physically interacts with both isoforms of STAT1, STAT1α and STAT1β through its macro domains in an ADP-ribosylation dependent manner. BAL1 directly inhibits together with STAT1β the expression of tumor suppressor and interferon response factor (IRF)-1. Conversely, BAL1 enhances the expression of the proto-oncogenes IRF2 and B-cell CLL/lymphoma (BCL)-6 in DLBCL. Our results show the first time that BAL1 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-53 axes and mediates proliferation, survival and chemo-resistance in DLBCL. As a consequence constitutive IFNγ-STAT1 signaling does not lead to apoptosis but rather to chemo-resistance in DLBCL overexpressing BAL1. Our results suggest that BAL1 may induce an oncogenic switch in STAT1 from a tumor suppressor to an oncogene in high-risk DLBCL.Journal of Cell Science 03/2013; 126(9). DOI:10.1242/jcs.118174 · 5.33 Impact Factor