GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo

• Published in: Blood Vol. 127; no. 22; pp. 2723 - 2731
• Main Authors: Healy, Jane A., Nugent, Adrienne, Rempel, Rachel E., Moffitt, Andrea B., Davis, Nicholas S., Jiang, Xiaoyu, Shingleton, Jennifer R., Zhang, Jenny, Love, Cassandra, Datta, Jyotishka, McKinney, Matthew E., Tzeng, Tiffany J., Wettschureck, Nina, Offermanns, Stefan, Walzer, Katelyn A., Chi, Jen-Tsan, Rasheed, Suhail A.K., Casey, Patrick J., Lossos, Izidore S., Dave, Sandeep S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-06-2016; American Society of Hematology
• Subjects: Animals; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Germinal Center - metabolism; Germinal Center - pathology; GTP-Binding Protein alpha Subunits - genetics; GTP-Binding Protein alpha Subunits - metabolism; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Heavy Chains - metabolism; Immunoglobulin Variable Region - genetics; Immunoglobulin Variable Region - metabolism; Lymphoid Neoplasia; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Male; Mice; Mice, Knockout; Proto-Oncogene Proteins c-myc - biosynthesis; Proto-Oncogene Proteins c-myc - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-07-659938

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.
•In mice, loss of GNA13 in GC B cells protects against cell death and may promote genetic instability via ongoing somatic hypermutation.•Gna13 loss, in combination with MYC overexpression, promotes lymphoma in mice.