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Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates irradiation–induced thymic lymphoma development

¹ Division of Developmental Immunology, Biocenter, Innsbruck Medical University, 6020 Innsbruck, Austria
² The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia

CORRESPONDENCE Andreas Villunger: andreas.villunger{at}i-med.ac.at

Members of the Bcl-2 protein family play crucial roles in the maintenance of tissue homeostasis by regulating apoptosis in response to developmental cues or exogenous stress. Proapoptotic BH3-only members of the Bcl-2 family are essential for initiation of cell death, and they function by activating the proapoptotic Bcl-2 family members Bax and/or Bak, either directly or indirectly through binding to prosurvival Bcl-2 family members. Bax and Bak then elicit the downstream events in apoptosis signaling. Mammals have at least eight BH3-only proteins and they are activated in a stimulus-specific, as well as a cell type–specific, manner. We have generated mice lacking the BH3-only protein Bcl-2–modifying factor (Bmf) to investigate its role in cell death signaling. Our studies reveal that Bmf is dispensable for embryonic development and certain forms of stress-induced apoptosis, including loss of cell attachment (anoikis) or UV irradiation. Remarkably, loss of Bmf protected lymphocytes against apoptosis induced by glucocorticoids or histone deacetylase inhibition. Moreover, bmf^–/– mice develop a B cell–restricted lymphadenopathy caused by the abnormal resistance of these cells to a range of apoptotic stimuli. Finally, Bmf-deficiency accelerated the development of irradiation–induced thymic lymphomas. Our results demonstrate that Bmf plays a critical role in apoptosis signaling and can function as a tumor suppressor.

A. Strasser and A. Villunger contributed equally to this paper.

M. Erlacher's present address is Dept. of Pediatrics and Adolescent Medicine, University Hospital of Freiburg, 79104 Freiburg, Germany.

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This article has been cited by other articles:

• Huntington, N. D., Labi, V., Cumano, A., Vieira, P., Strasser, A., Villunger, A., Di Santo, J. P., Alves, N. L. (2009). Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim sustains B lymphopoiesis in the absence of IL-7. Int Immunol 21: 715-725 [Abstract] [Full Text]  

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