title: Conditional knockdown of BCL2A1 reveals rate-limiting roles in BCR-dependent B-cell survival.
abstract: Bcl2 family proteins control mitochondrial apoptosis and its members exert critical cell type and differentiation stage-specific functions, acting as barriers against autoimmunity or transformation. Anti-apoptotic Bcl2a1/Bfl1/A1 is frequently deregulated in different types of blood cancers in humans but its physiological role is poorly understood as quadruplication of the Bcl2a1 gene locus in mice hampers conventional gene targeting strategies. Transgenic overexpression of A1, deletion of the A1-a paralogue or constitutive knockdown in the hematopoietic compartment of mice by RNAi suggested rate-limiting roles in lymphocyte development, granulopoiesis and mast cell activation. Here we report on the consequences of conditional knockdown of A1 protein expression using a reverse transactivator (rtTA)-driven approach that highlights a critical role for this Bcl2 family member in the maintenance of mature B-cell homeostasis. Furthermore, we define the A1/Bim (Bcl-2 interacting mediator of cell death) axis as a target of key kinases mediating B-cell receptor (BCR)-dependent survival signals, such as, spleen tyrosine kinase (Syk) and Brutons tyrosine kinase (Btk). As such, A1 represents a putative target for the treatment of B-cell-related pathologies depending on hyperactivation of BCR-emanating survival signals and loss of A1 expression accounts, in part, for the pro-apoptotic effects of Syk- or Btk inhibitors that rely on the 'BH3-only' protein Bim for cell killing.
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Sochalska
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Ottina
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Tuzlak
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Herzog
authors.affiliation: The Walter and Eliza Hall Institute for Medical Research, University of Melbourne, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Herold
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Villunger
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D000072377:Syk Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse