SAT-LB056 Is AIP a Tumor Suppressor or an Oncogene? AIP as a Novel Regulator of the Oncogene BCL6 in Diffuse Large B Cell Lymphoma

Abstract

Background: Heterozygous germline loss-of-function mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are usually associated with acromegaly or gigantism due to a young-onset somatotropinoma. AIP functions as a tumor suppressor gene in the pituitary, while its role in other tumours is unknown. AIP is highly expressed in patients with Diffuse Large B Cell Lymphoma (DLBCL) compared to any other tumor type. DLBCL arises from germinal centre B cells which characteristically express the transcriptional repressor B cell lymphoma-6 (BCL6), key for germinal centre formation. Increased expression of BCL6 can lead to the development of DLBCL. Despite the obvious importance of BCL6 expression in GC B cells, the mechanisms by which it is regulated are still poorly understood. Aim: The aim of this study was to investigate the relationship of the high AIP expression, BCL6 and the pathobiology of DLBCL. Methods: We generated mice carrying a conditional homozygous deletion of Aip in T and B cells (Aipfl/fl;Rag1Cre/+). Co-localization of AIP and members of the BCL6 ubiquitination/proteasome pathway by immunofluorescence analysis. Ubiquitin-mediated proteasomal degradation study was done by immuno-precipitation (IP). Results: Our study found that AIP is highly expressed in DLBCL. Genetic deletion of Aip revealed that AIP supported BCL6 expression in mice. The ubiquitin E3 ligase FBXO11 has been previously shown to add ubiquitin to BCL6. We found that AIP could bind to the deubiquitinase UCHL1 and that UCHL1 could remove ubiquitin from BCL6 thereby supporting BCL6 expression by preventing FBXO11 mediated degradation of BCL6 recapitulating what we observed in Aip deficient B cells. Conclusions: The data presented here reveal AIP to be a novel positive regulator of BCL6 protein expression which is commonly up-regulated in DLBCL and prevents FBXO11 degradation of BCL6 by enabling the UCHL1 to remove ubiquitin from BCL6. Therefore, AIP is a potential novel therapeutic target to treat DLBCL. It appears that AIP function as a tumor suppressor in the pituitary and as an oncogene to the pathobiology of DLBCL. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.