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

Authors :
Healy, Jane A.
Nugent, Adrienne
Rempel, Rachel E.
Moffitt, Andrea B.
Davis, Nicholas S.
Xiaoyu Jiang
Shingleton, Jennifer R.
Zhang, Jenny
Love, Cassandra
Datta, Jyotishka
McKinney, Matthew E.
Tzeng, Tiffany J.
Wettschureck, Nina
Offermanns, Stefan
Walzer, Katelyn A.
Jen-Tsan Chi
Rasheed, Suhail A. K.
Casey, Patrick J.
Lossos, Izidore S.
Dave, Sandeep S.
Source :
Blood. 6/2/2016, Vol. 127 Issue 22, p2723-2731. 9p.
Publication Year :
2016

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00064971
Volume :
127
Issue :
22
Database :
Academic Search Index
Journal :
Blood
Publication Type :
Academic Journal
Accession number :
115868979
Full Text :
https://doi.org/10.1182/blood-2015-07-659938