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 lymphomas1,2. 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 disease3,4. 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.

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

“…This finding argues that there is something special about solid tumors that selects for loss of function mutations. Some of the CISs that we identified may represent haploinsufficient tumor suppressors, a recent example being Fbxo11 in B-cell lymphoma (46). Alternatively, acquired point mutation, rearrangement, or epigenetic silencing may be the preferred mechanism for inactivating the second allele in solid tumors.…”

Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma

“…Of the >35 human F-box proteins, only two resemble DRE-1 in containing a carbohydrate-binding proteins and sugar hydrolases (CASH) domain: FBXO10 and FBXO11. FBXO11 has been shown to control the levels of the BCL6 transcriptional regulator and is confined to the nucleus, making it unlikely to be a regulator of BCL2, which resides in the cytoplasm (20). A Flag epitope-tagged FBXO10 isoform was localized in the cytoplasm of transduced HEK293T cells (Fig.…”

FBH1 protects melanocytes from transformation and is deregulated in melanomas

“…Genomic DNA from the MZ7 cell line was prepared as previously described. 15 Exons containing potential mutations in the FBH1 gene were amplified using PCR and sequenced. The reference sequence of FBH1 was obtained from the UCSC Human Genome database (mRNA accession NM_032807.3).…”