Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival

J Exp Med. 2017 Feb;214(2):491-510. doi: 10.1084/jem.20160869. Epub 2017 Jan 5.


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) levels in both control and BCL2-null mice. Finally, we showed that deletion of BIM restored survival in BCL2-deficient but not MCL1-deficient NK cells. Overall, these data demonstrate an essential role for the binding of BCL2 to BIM in the survival of noncycling NK cells. They also favor a model in which MCL1 is the dominant survival protein in proliferating NK cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / physiology
  • Bcl-2-Like Protein 11 / physiology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Cycle
  • Cell Survival
  • Female
  • Killer Cells, Natural / physiology*
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Natural Cytotoxicity Triggering Receptor 1 / physiology
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Sulfonamides / pharmacology


  • Antigens, Ly
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Bridged Bicyclo Compounds, Heterocyclic
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • venetoclax