期刊
BLOOD
卷 115, 期 5, 页码 995-1005出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-03-212670
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资金
- Association for International Cancer Research (AICR) [06-440]
- Austrian Science Fund [SFB021]
- ONCOTYROL
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 BH3only 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 E mu-myc/bmf(-/-) mice, whereas E mu-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. (Blood. 2010;115:995-1005)
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