title: 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.
authors: Department of Pathology, NYU Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
authors: Shanshan
authors: S
authors: Duan
authors: Lukas
authors: L
authors: Cermak
authors: Julia K
authors: JK
authors: Pagan
authors: Mario
authors: M
authors: Rossi
authors: Cinzia
authors: C
authors: Martinengo
authors: Paola Francia
authors: PF
authors: di Celle
authors: Bjoern
authors: B
authors: Chapuy
authors: Margaret
authors: M
authors: Shipp
authors: Roberto
authors: R
authors: Chiarle
authors: Michele
authors: M
authors: Pagano
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D011484:Protein-Arginine N-Methyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D059748:Proteolysis; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; C457579:FBXO11 protein, human; D011484:Protein-Arginine N-Methyltransferases; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex