4.7 Article

Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3-only proteins Bim and Bmf

Journal

BLOOD
Volume 123, Issue 17, Pages 2652-2662

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-11-537217

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Funding

  1. Austrian Science Fund [P23510-B19, Y212-B13]
  2. National Health and Medical Research Council Australia
  3. Leukemia and Lymphoma Society (Specialized Center of Research grant)
  4. Cancer Council of Victoria
  5. Tyrolean Science Fund
  6. Osterreichische Krebshilfe-Tirol
  7. Doc-fFORTE doctoral fellowship from the Austrian Academy of Science
  8. Austrian Science Fund (FWF) [P 23510] Funding Source: researchfish
  9. Austrian Science Fund (FWF) [P23510] Funding Source: Austrian Science Fund (FWF)

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BH3 domain-only proteins (BH3-only) proteins are members of the Bcl-2 family that play crucial roles in embryogenesis and the maintenance of tissue homeostasis by triggering apoptotic cell death. The BH3-only protein Bim is critical for developmental apoptosis of lymphocytes, securing establishment of tolerance and for the termination of immune responses. Bim is believed to act in concert with other BH3-only proteins or members of the tumor necrosis factor receptor family in getting rid of unwanted cells. Bmf, a related BH3-only protein, was shown to play a role in B-cell homeostasis and to mediate cell death in response to certain apoptotic triggers, including glucocorticoid, histone deacetylase inhibitors, and overexpression of the c-Myc proto-oncogene. Here we show that Bim and Bmf have overlapping functions during mouse development and coregulate lymphocyte homeostasis and apoptosis in a nonredundant manner. Double deficiency of Bim and Bmf caused more B lymphadenopathy than loss of either BH3-only protein alone, and this was associated with autoimmune glomerulonephritis and a range of malignancies in aged mice. Thus, our results demonstrate that Bim and Bmf act in concert to prevent autoimmunity and malignant disease, strengthening the rational for the development of BH3-only protein mimicking therapeutics for the treatment of such disorders.

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