FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas

Department of Pathology, NYU Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
Nature (Impact Factor: 41.46). 11/2011; 481(7379):90-3. DOI: 10.1038/nature10688
Source: PubMed

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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    • "Our results identify FBXO11 as an important miR-21 target gene. In addition, there was an inverse relationship between FBXO11 and BCL6 expression in various human cancer cell lines, and FBXO11 overexpression resulted in markedly lower BCL6 levels, which is consistent with the finding that FBXO11 directly mediates BCL6 degradation [Duan et al., 2012]. Although the role of BCL6 in lymphoma is fairly well defined [Parekh et al., 2007], these findings suggest that BCL6 may also play an important role in non-lymphoid cancers as well. "
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    Drug Development Research 06/2015; DOI:10.1002/ddr.21257 · 0.77 Impact Factor
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    • "TP53 responds to diverse cellular stresses by regulating the expression of specific target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair or metabolic changes (Dai and Gu 2010; Lane 1992). An example of cluster 1 protein is the F-box protein FBOX11, which interacts with the E3 ubiquitin–protein ligase complex that mediates ubiquitination and subsequent proteasomal degradation of target proteins involved in diverse biological process (Duan et al. 2012), which therefore can be predicted to be sensitive to zinc availability . Of the 20 top ZNBPs in cluster 3, twelve are involved in gene expression either directly, as transcription factors (tumor suppressor genes P53, P63, BCL6, SSH, PML, SMAD2, SMAD3, SMAD4, SMAD7), or indirectly, as regulators of the DNA dwelling or DNA repair processes (HDAC4, HDAC5, BRCA1). "
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    • "and MYC have been previously described in BL (Johnston and Carroll, 1992; Wilda et al., 2004) and changes in FBXO11 (Duan et al., 2012) and DDX3X (Wang et al., 2011) have been recently characterized in other B-cell malignancies, like diffuse large B-cell lymphomas (DLBCL), and chronic lymphocytic leukemia, respectively. Moreover , recent studies showed ID3 mutations to activate the PI3-kinase pathway in BLs (Love et al., 2012; Richter et al., 2012; Schmitz et al., 2012). "
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