Suppression of B-cell lymphomagenesis by the BH3-only proteins Bmf and Bad.
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 Emu-myc/bmf(-/-) mice, whereas Emu-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.
Frenzel
Anna
A
Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
Labi
Verena
V
Chmelewskij
Waldemar
W
Ploner
Christian
C
Geley
Stephan
S
Fiegl
Heidelinde
H
Tzankov
Alexandar
A
Villunger
Andreas
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D005260:Female; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D013997:Time Factors; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C494820:Bad protein, mouse; C435486:Bmf protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051025:bcl-Associated Death Protein