FBXO11 Inactivation Leads to Abnormal Germinal-center Formation and Lymphoproliferative Disease

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2016 May 12

PMID 27166359

Citations 30

Authors

Christof Schneider

Ning Kon

Letizia Amadori

Qiong Shen

Friederike H Schwartz

Benjamin Tischler

Marion Bossennec

David Dominguez-Sola

Govind Bhagat

Wei Gu

Katia Basso

Riccardo Dalla-Favera

Affiliations

Soon will be listed here.

Abstract

The BCL6 proto-oncogene encodes a transcriptional repressor that is required for the germinal center (GC) reaction and is implicated in lymphomagenesis. BCL6 protein stability is regulated by F-box protein 11 (FBXO11)-mediated ubiquitination and degradation, which is impaired in ∼6% of diffuse large B-cell lymphomas that carry inactivating genetic alterations targeting the FBXO11 gene. In order to investigate the role of FBXO11 in vivo, we analyzed GC-specific FBXO11 knockout mice. FBXO11 reduction or loss led to an increased number of GC B cells, to an altered ratio of GC dark zone to light zone cells, and to higher levels of BCL6 protein in GC B cells. B-cell receptor-mediated degradation of BCL6 was reduced in the absence of FBXO11, suggesting that FBXO11 contributes to the physiologic downregulation of BCL6 at the end of the GC reaction. Finally, FBXO11 inactivation was associated with the development of lymphoproliferative disorders in mice.

Citing Articles

Ubiquitin-specific peptidases in lymphoma: a path to novel therapeutics.

Samareh Salavatipour M, Tavakoli S, Halimi A, Tavoosi S, Baghsheikhi A, Talebi-Taheri A Front Pharmacol. 2024; 15:1356634.

PMID: 39664521 PMC: 11632177. DOI: 10.3389/fphar.2024.1356634.

Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation.

Nakagawa R, Llorian M, Varsani-Brown S, Chakravarty P, Camarillo J, Barry D Nat Commun. 2024; 15(1):10516.

PMID: 39627218 PMC: 11615350. DOI: 10.1038/s41467-024-54937-0.

The F-box E3 ligase protein FBXO11 regulates EBNA3C-associated degradation of BCL6.

Sun K, Bose D, Singh R, Pei Y, Robertson E J Virol. 2024; 98(7):e0054824.

PMID: 38864622 PMC: 11265398. DOI: 10.1128/jvi.00548-24.

Mouse models of diffuse large B cell lymphoma.

Tabatabai A, Arora A, Hofmann S, Jauch M, von Tresckow B, Hansen J Front Immunol. 2023; 14:1313371.

PMID: 38124747 PMC: 10731046. DOI: 10.3389/fimmu.2023.1313371.

Proteomic and Bioinformatic Tools to Identify Potential Hub Proteins in the Audiogenic Seizure-Prone Hamster GASH/Sal.

Garcia-Peral C, Ledesma M, Herrero-Turrion M, Gomez-Nieto R, Castellano O, Lopez D Diagnostics (Basel). 2023; 13(6).

PMID: 36980356 PMC: 10047193. DOI: 10.3390/diagnostics13061048.

References

Mandelbaum J, Bhagat G, Tang H, Mo T, Brahmachary M, Shen Q . BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell. 2010; 18(6):568-79. PMC: 3030476. DOI: 10.1016/j.ccr.2010.10.030. View

Alizadeh A, Eisen M, Davis R, Ma C, Lossos I, Rosenwald A . Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403(6769):503-11. DOI: 10.1038/35000501. View

Nakayama K, Nakayama K . Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 2006; 6(5):369-81. DOI: 10.1038/nrc1881. View

Niu H, Ye B, Dalla-Favera R . Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 1998; 12(13):1953-61. PMC: 316953. DOI: 10.1101/gad.12.13.1953. View

Victora G, Nussenzweig M . Germinal centers. Annu Rev Immunol. 2012; 30:429-57. DOI: 10.1146/annurev-immunol-020711-075032. View

Forbes S, Bindal N, Bamford S, Cole C, Kok C, Beare D . COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2010; 39(Database issue):D945-50. PMC: 3013785. DOI: 10.1093/nar/gkq929. View

De Silva N, Klein U . Dynamics of B cells in germinal centres. Nat Rev Immunol. 2015; 15(3):137-48. PMC: 4399774. DOI: 10.1038/nri3804. View

Duan S, Cermak L, Pagan J, Rossi M, Martinengo C, Francia di Celle P . FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature. 2011; 481(7379):90-3. PMC: 3344385. DOI: 10.1038/nature10688. View

Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V . Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011; 471(7337):189-95. PMC: 3271441. DOI: 10.1038/nature09730. View

10.

Skaar J, Pagan J, Pagano M . Mechanisms and function of substrate recruitment by F-box proteins. Nat Rev Mol Cell Biol. 2013; 14(6):369-81. PMC: 3827686. DOI: 10.1038/nrm3582. View

11.

Saito M, Gao J, Basso K, Kitagawa Y, Smith P, Bhagat G . A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell. 2007; 12(3):280-92. DOI: 10.1016/j.ccr.2007.08.011. View

12.

Lohr J, Stojanov P, Lawrence M, Auclair D, Chapuy B, Sougnez C . Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012; 109(10):3879-84. PMC: 3309757. DOI: 10.1073/pnas.1121343109. View

13.

Casola S, Cattoretti G, Uyttersprot N, Koralov S, Seagal J, Segal J . Tracking germinal center B cells expressing germ-line immunoglobulin gamma1 transcripts by conditional gene targeting. Proc Natl Acad Sci U S A. 2006; 103(19):7396-401. PMC: 1464351. DOI: 10.1073/pnas.0602353103. View

14.

Scuoppo C, Miething C, Lindqvist L, Reyes J, Ruse C, Appelmann I . A tumour suppressor network relying on the polyamine-hypusine axis. Nature. 2012; 487(7406):244-8. PMC: 3530829. DOI: 10.1038/nature11126. View

15.

Bornkamm G, Berens C, Kuklik-Roos C, Bechet J, Laux G, Bachl J . Stringent doxycycline-dependent control of gene activities using an episomal one-vector system. Nucleic Acids Res. 2005; 33(16):e137. PMC: 1201338. DOI: 10.1093/nar/gni137. View

16.

Cattoretti G, Pasqualucci L, Ballon G, Tam W, Nandula S, Shen Q . Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell. 2005; 7(5):445-55. DOI: 10.1016/j.ccr.2005.03.037. View

17.

Basso K, Dalla-Favera R . Germinal centres and B cell lymphomagenesis. Nat Rev Immunol. 2015; 15(3):172-84. DOI: 10.1038/nri3814. View

18.

Basso K, Dalla-Favera R . Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev. 2012; 247(1):172-83. DOI: 10.1111/j.1600-065X.2012.01112.x. View

19.

Fellmann C, Zuber J, McJunkin K, Chang K, Malone C, Dickins R . Functional identification of optimized RNAi triggers using a massively parallel sensor assay. Mol Cell. 2011; 41(6):733-46. PMC: 3130540. DOI: 10.1016/j.molcel.2011.02.008. View

20.

Pasqualucci L, Khiabanian H, Fangazio M, Vasishtha M, Messina M, Holmes A . Genetics of follicular lymphoma transformation. Cell Rep. 2014; 6(1):130-40. PMC: 4100800. DOI: 10.1016/j.celrep.2013.12.027. View