title: Bfl-1 is a crucial pro-survival nuclear factor-κB target gene in Hodgkin/Reed-Sternberg cells.
abstract: Hodgkin/Reed-Sternberg (H/RS) cells are believed to represent clonal progeny of Germinal Centre B cells that have escaped negative selection by evading apoptosis. Aberrant constitutive activity of the transcription factor NF-κB plays a key role in the pathogenesis of Hodgkin's Lymphoma (HL), conferring a survival advantage on H/RS cells. Bfl-1 is a pro-survival NF-κB target gene from the Bcl-2 family of apoptosis-regulating proteins. Here, we report that bfl-1 (also known as A1 or GRS) is frequently expressed in primary H/RS cells from HL tumor biopsies and that elevated bfl-1 expression is a feature of H/RS derived cell lines. We show that bfl-1 is an NF-κB target gene in this cell context and that this regulation is effected through a p65-binding DNA element located in its promoter. We demonstrate that ectopic Bfl-1 can rescue cultured H/RS cells from apoptosis induced by pharmacological inhibitors of NF-κB, and that knockdown of bfl-1 potentiates the pro-apoptotic effect of these agents. These findings are the first indication that Bfl-1 plays a crucial role in setting the elevated threshold of resistance of this malignant cell type to apoptosis.
authors.affiliation: School of Biotechnology and National Centre for Sensor Research, Dublin City University, Dublin 9, Ireland.
authors.forename: Sinéad T
authors.initials: ST
authors.lastname: Loughran
authors.forename: Eva M
authors.initials: EM
authors.lastname: Campion
authors.forename: Brendan N
authors.initials: BN
authors.lastname: D'Souza
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Smith
authors.forename: Katerina
authors.initials: K
authors.lastname: Vrzalikova
authors.forename: Kaisheng
authors.initials: K
authors.lastname: Wen
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
authors.forename: Dermot
authors.initials: D
authors.lastname: Walls
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000378:metabolism*
chemical_list: C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2