Suppression of B-cell lymphomagenesis by the BH3-only proteins Bmf and Bad

Frenzel, Anna; Labi, Verena; Chmelewskij, Waldemar; Ploner, Christian; Geley, Stephan; Fiegl, Heidelinde; Tzankov, Alexandar; Villunger, Andreas

doi:10.1182/blood-2009-03-212670

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Journal article

Suppression of B-cell lymphomagenesis by the BH3-only proteins Bmf and Bad

Frenzel, Anna Division of Developmental Immunology and
Labi, Verena Division of Developmental Immunology and
Chmelewskij, Waldemar Division of Developmental Immunology and
Ploner, Christian Division of Molecular Pathophysiology, Biocenter, Innsbruck Medical University, Innsbruck, Austria;
Geley, Stephan Division of Molecular Pathophysiology, Biocenter, Innsbruck Medical University, Innsbruck, Austria;
Fiegl, Heidelinde Department of Obstetrics and Gynecology, Innsbruck University Hospital, Innsbruck, Austria; and
Tzankov, Alexandar Institute of Pathology, University of Basel, Basel, Switzerland
Villunger, Andreas Division of Developmental Immunology and

Published in:

Blood. - American Society of Hematology. - 2010, vol. 115, no. 5, p. 995-1005

English Abstract
Oncogenic c-Myc is known to balance excessive proliferation by apoptosis that can be triggered by p53-dependent and p53-independent signaling networks. Here, we provide evidence that the BH3-only proapoptotic Bcl-2 family members Bcl-2 modifying factor (Bmf) and Bcl-2 antagonist of cell death (Bad) are potent antagonists of c-Myc–driven B-cell lymphomagenesis. Tumor formation was preceded by the accumulation of preneoplastic pre-B and immature immunoglobulin M–positive (IgM+) B cells in hematopoietic organs of Eμ-myc/bmf−/− mice, whereas Eμ-myc/bad−/− mice showed an increase of pre-B cells limited to the spleen. Although the loss of Bad had no impact on the tumor immunophenotype, Bmf deficiency favored the development of IgM+ B cell over pre-B cell tumors. This phenomenon was caused by a strong protection of immature IgM+ B cells from oncogene-driven apoptosis caused by loss of bmf and c-Myc–induced repression of Bmf expression in premalignant pre-B cells. Steady-state levels of B-cell apoptosis also were reduced in the absence of Bad, in support of its role as a sentinel for trophic factor-deprivation. Loss of Bmf reduced the pressure to inactivate p53, whereas Bad deficiency did not, identifying Bmf as a novel component of the p53-independent tumor suppressor pathway triggered by c-Myc.

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