Journal article
Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival
C Viant, S Guia, RJ Hennessy, J Rautela, K Pham, C Bernat, W Goh, Y Jiao, R Delconte, M Roger, V Simon, F Souza-Fonseca-Guimaraes, S Grabow, GT Belz, BT Kile, A Strasser, D Gray, PD Hodgkin, B Beutler, E Vivier Show all
Journal of Experimental Medicine | ROCKEFELLER UNIV PRESS | Published : 2017
DOI: 10.1084/jem.20160869
Abstract
Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells. Consistent with this, cycling NK cells expressed higher MCL1 (myeloid cell leukemia 1) l..
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Awarded by Australian Research Council
Funding Acknowledgements
This work is supported by program and project grants from the National Health and Medical Research Council (NHMRC) of Australia (1049407, 1066770, 1057852, and 1027472 to N.D. Huntington; 1047903 and 1027472 to G.T. Belz; 1078763 to D. Gray; 1016701 to A. Strasser; and 1057831 and 1054925 to K. Pham and P.D. Hodgkin), as well as an NHMRC Independent Research Institute Infrastructure Support Scheme grant and a Victorian State Government Operational Infrastructure Scheme grant. N.D. Huntington is a recipient of a Melanoma Research Grant from the Harry J. Lloyd Charitable Trust and a CLIP grant from Cancer Research Institute. A. Strasser and D. Gray hold a Cancer Council Victoria (CCV) Grant in Aid (1102104). This work is also supported by fellowships from the NHMRC (GNT0461276 to N.D. Huntington, 1090236 to D. Gray, and 1020363 to A. Strasser), the Australian Research Council (to G.T. Belz), the Leukemia and Lymphoma Society (SCOR grant 7413 to A. Strasser and D. Gray), the CCV (1052309 to A. Strasser), and the Menzies Foundation (to N.D. Huntington). This work is also supported by grants from the French Agence Nationale de la Recherche (ANR-JC07-206305 and ANR-08-JCJC-0016) and the European Research Council (THINK Advanced Grant to E. Vivier) and by institutional grants from Institut National de la Sante et de la Recherche Medicale, Centre National de la Recherche Scientifique, and Aix-Marseille Universite to CIML (S. Ugolini and E. Vivier laboratory). This study was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHM RC Independent Research Institute Infrastructure Support scheme. E. Vivier is a scholar of the Institut Universitaire de France. Whole-exome captures and high-throughput sequencing and analysis were performed at the Transcriptomique et Genomique de Marseille-Luminy (TGML) Platform, which is supported by grants from IBiSA, Aix-Marseille Universite, and the "Investissements d'Avenir" program France Genomique ANR-10-INBS-0009-10.