Frenzel, Anna Labi, Verena Chmelewskij, Waldemar Ploner, Christian Geley, Stephan Fiegl, Heidelinde Tzankov, Alexandar Villunger, Andreas <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> application/pdf https://sonar.ch/global/documents/94122 eng info:eu-repo/semantics/altIdentifier/doi/10.1182/blood-2009-03-212670 info:eu-repo/semantics/altIdentifier/issn/0006-4971 info:eu-repo/semantics/openAccess Blood. - American Society of Hematology. - 2010, vol. 115, no. 5, p. 995-1005 Immunology Cell Biology Biochemistry Hematology Suppression of B-cell lymphomagenesis by the BH3-only proteins Bmf and Bad http://purl.org/coar/resource_type/c_6501