title: Transcriptional and post-transcriptional mechanisms of BAFF-receptor dysregulation in human B lineage malignancies.
abstract: Together, circulating BAFF and dominant receptor BAFF-R homeostatically regulate the humoral immune system. Consistently aberrant BAFF-R expression in leukemic cells reveals an intimate connection of these cells' malignant physiology to the BAFF/BAFF-R axis and also provides an additional survival mechanism to the expressing cells. In this study, we used primary cells and cell lines to interrogate the mechanisms underlying aberrant BAFF-R expression in precursor B acute lymphoblastic leukemia (precursor B-ALL) and mature B chronic lymphocytic leukemia (CLL). Here we demonstrate the aberrant expression of BAFF-R in precursor B-ALL cell lines and reveal that these cells acquire BAFF-R expression through premature transcriptional activation of the BAFF-R promoter in coordination with regulatory transcription factor c-Rel. Investigations using primary CLL cells provide a crucial counterpoint through their paucity of BAFF-R relative to their benign mature B cell counterparts, which we establish as functionally significant in its depletion of the CLL cells' BAFF-binding capacity. Furthermore, BAFF-R downregulation in CLL patients is revealed here to be restricted to the malignant compartment and mediated post-transcriptionally in order to compensate for the consistently unchanged levels of transcription factor c-Rel and BAFF-R mRNA. Finally, we present evidence that CLL cells retain endogenous mechanisms of BAFF-R regulatory control despite active receptor dysregulation.
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Mihalcik
authors.forename: Renee C
authors.initials: RC
authors.lastname: Tschumper
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
mesh_terms: D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology / Q000503:physiopathology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology / Q000503:physiopathology*; D012323:RNA Processing, Post-Transcriptional; D014158:Transcription, Genetic
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor