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)reactionandis implicatedin lymphomagenesis.BCL6proteinstability 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 increasednumber of GCB 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.