title: GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo.
abstract: GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre(+) GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Jane A
authors.initials: JA
authors.lastname: Healy
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Adrienne
authors.initials: A
authors.lastname: Nugent
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Rempel
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Moffitt
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Davis
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL;
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Shingleton
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Cassandra
authors.initials: C
authors.lastname: Love
authors.affiliation: Department of Statistics, Duke University, Durham, NC;
authors.forename: Jyotishka
authors.initials: J
authors.lastname: Datta
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Matthew E
authors.initials: ME
authors.lastname: McKinney
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Tiffany J
authors.initials: TJ
authors.lastname: Tzeng
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC; and.
authors.forename: Katelyn A
authors.initials: KA
authors.lastname: Walzer
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC; and.
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Suhail A K
authors.identifier: 0000-0002-7674-7560
authors.initials: SA
authors.lastname: Rasheed
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Casey
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL;
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dave
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc