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

Nature volume 481, pages 90–93 (2012)Cite this article

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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.

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Figure 1: FBXO11 controls the ubiquitylation and degradation of BCL6.
Figure 2: DLBCL cell lines with FBXO11 deletions or an FBXO11 mutation display increased levels and stability of BCL6.
Figure 3: Human DLBCLs with FBXO11 mutations display increased levels of BCL6, and FBXO11 tumour-derived mutants have impaired abilities to induce BCL6 degradation.
Figure 4: Expression of FBXO11 in FBXO11 -null cells promotes BCL6 ubiquitylation and degradation, inhibits cell proliferation and induces apoptosis.

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  • 04 January 2012

    The labelling of Fig. 1a was corrected.

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Acknowledgements

We thank W. Carroll, S. Shaham and L. Staudt for sharing unpublished results; A. Melnick, Y. Sun and Y. Xiong for reagents; L. Cerchietti, Y. Cheng, E. Dehan, V. Donato, N. V. Dorello, S. N. Yang and Z. Yao for advice and/or contributions to this work. M.P. is grateful to T. M. Thor and K. E. Davidson, and L.C. to Zuzana S. for continuous support. This work was supported by grants from the National Institutes of Health to M.P. (R01-GM57587, R37-CA76584 and R21-CA161108) and M.S. (PO1-CA092625), a grant from Susan G. Komen for the Cure to S.D., a Lymphoma Research Foundation Fellowship to J.K.P. and grants from AIRC and ERC (ERC-2009-StG-Proposal No242965-LUNELY) to R.C. M.P. is an Investigator with the Howard Hughes Medical Institute.

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Author notes

  1. Shanshan Duan and Lukas Cermak: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA,

    Shanshan Duan, Lukas Cermak, Julia K. Pagan, Mario Rossi & Michele Pagano

  2. Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA ,

    Shanshan Duan, Lukas Cermak, Julia K. Pagan & Michele Pagano

  3. Department of Biomedical Sciences and Human Oncology, CERMS, University of Torino, 10126 Torino, Italy,

    Cinzia Martinengo & Roberto Chiarle

  4. San Giovanni Battista Hospital, Via Santena 7, 10126 Torino, Italy ,

    Paola Francia di Celle

  5. Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA ,

    Bjoern Chapuy & Margaret Shipp

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Contributions

S.D., L.C. and J.K.P. planned and performed most experiments and helped to write the manuscript. M.P. coordinated the study, oversaw the results and wrote the manuscript. C.M., P.F.d.C. and R.C. provided the DLBCL tumour samples and some DLBCL cell lines, and performed some experiments. M.R. generated several constructs. B.C. and M.S. provided the HD-SNP data in Supplementary Fig. 10. All authors discussed the results and commented on the manuscript.

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Correspondence to Roberto Chiarle or Michele Pagano.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-14 with legends, Supplementary Tables 1-3 and additional references. (PDF 9357 kb)

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Duan, S., Cermak, L., Pagan, J. et al. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature 481, 90–93 (2012). https://doi.org/10.1038/nature10688

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