title: FBXO11 inactivation leads to abnormal germinal-center formation and lymphoproliferative disease.
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.
authors.affiliation: Institute for Cancer Genetics.
authors.forename: Christof
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Institute for Cancer Genetics.
authors.forename: Ning
authors.initials: N
authors.lastname: Kon
authors.affiliation: Institute for Cancer Genetics.
authors.forename: Letizia
authors.initials: L
authors.lastname: Amadori
authors.affiliation: Institute for Cancer Genetics.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Institute for Cancer Genetics.
authors.forename: Friederike H
authors.initials: FH
authors.lastname: Schwartz
authors.affiliation: Institute for Cancer Genetics.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tischler
authors.affiliation: Institute for Cancer Genetics.
authors.forename: Marion
authors.initials: M
authors.lastname: Bossennec
authors.affiliation: Institute for Cancer Genetics.
authors.forename: David
authors.initials: D
authors.lastname: Dominguez-Sola
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, The Herbert Irving Comprehensive Cancer Center.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, The Herbert Irving Comprehensive Cancer Center.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology.
authors.forename: Katia
authors.initials: K
authors.lastname: Basso
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, The Herbert Irving Comprehensive Cancer Center, Department of Microbiology and Immunology, and Department of Genetics and Development, Columbia University, New York, NY.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D020868:Gene Silencing; D018390:Gene Targeting; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D018655:Lymphocyte Count; D008232:Lymphoproliferative Disorders / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009928:Organ Specificity; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism
chemical_list: C490010:Bcl6 protein, mouse; D044783:F-Box Proteins; C515669:Fbxo11 protein, mouse; D007075:Immunoglobulin M; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6