title: BCR-signaling-induced cell death demonstrates dependency on multiple BH3-only proteins in a murine model of B-cell lymphoma.
abstract: Genetic recombination during B-cell development regularly results in the generation of autoreactive, potentially pathogenic B-cell receptors (BCRs). Consequently, multiple mechanisms link inappropriate BCR specificity to clonal deletion. Similar pathways remain in malignant B cells, offering the potential for targeting BCR signaling. Recently, small molecule inhibitors have realized this potential and, therefore, a deeper understanding of BCR-induced signaling networks in malignant cells is vital. The BH3-only protein Bim has a key role in BCR-induced apoptosis, but it has long been proposed that additional BH3-only proteins also contribute, although conclusive proof has been lacking. Here, we comprehensively characterized the mechanism of BCR-induced apoptosis in Eμ-Myc murine lymphoma cells. We demonstrate the upregulation of Bim, Bik, and Noxa during BCR signaling in vitro and that intrinsic apoptosis has a prominent role in anti-BCR antibody therapy in vivo. Furthermore, lymphomas deficient in these individual BH3-only proteins display significant protection from BCR-induced cell death, whereas combined loss of Noxa and Bim offers enhanced protection in comparison with loss of Bim alone. Some but not all of these effects were reversed upon inhibition of Syk or MEK. These observations indicate that BCR signaling elicits maximal cell death through upregulation of multiple BH3-only proteins; namely Bim, Bik, and Noxa.
authors.affiliation: Antibody and Vaccine group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Carter
authors.affiliation: Antibody and Vaccine group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: K L
authors.initials: KL
authors.lastname: Cox
authors.affiliation: Antibody and Vaccine group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Blakemore
authors.affiliation: Antibody and Vaccine group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Y D
authors.initials: YD
authors.lastname: Bogdanov
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Happo
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia.
authors.forename: C L
authors.initials: CL
authors.lastname: Scott
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Cancer Sciences Unit, University of Southampton, Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: G K
authors.initials: GK
authors.lastname: Packham
authors.affiliation: Antibody and Vaccine group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: M S
authors.initials: MS
authors.lastname: Cragg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D016393:Lymphoma, B-Cell / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C111741:Bik protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr