Bim is a suppressor of Myc-induced mouse B cell leukemia
- Author(s)
- Egle, A; Harris, AW; Bouillet, P; Cory, S;
- Details
- Publication Year 2004-04-20,Volume 101,Issue #16,Page 6164-6169
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Publication Type
- Journal Article
- Abstract
- Impaired apoptosis is now recognized to be central to tumor development. Bcl2, activated by chromosomal translocation in human follicular lymphoma, promotes oncogenesis by inhibiting apoptosis. Bim, a distant proapoptotic relative, is emerging as a major physiologic antagonist of Bcl2. Here, we show that loss of Bim is oncogenic. Bim protein levels were elevated in the apoptosis-prone B lymphoid cells of Emu-Myc-transgenic mice, and Bim-mutant Emu-Myc mice had increased numbers of IgM-bearing B cells. Emu-Myc-expressing B lymphoid cells deficient in Bim were refractory to apoptosis induced in vitro by cytokine deprivation or antigen receptor cross-linking. Thus, Bim is induced by Myc in B cells and mediates apoptosis. Remarkably, inactivation of even a single allele of Bim accelerated Myc-induced development of tumors, particularly acute B cell leukemia. None of the primary tumors from Bim(+/-) Emu-Myc mice displayed loss of the second allele of Bim. These findings indicate that Bim is a tumor suppressor, at least in B lymphocytes, and is haploinsufficient. Whereas the p19Arf/p53 pathway is frequently mutated in tumors arising in Bim(+/+) Emu-Myc mice, it was unaffected in most Bim-deficient tumors, indicating that Bim reduction is an effective alternative to loss of p53 function.
- Publisher
- NATL ACAD SCIENCES
- Keywords
- BCL-2 RELATIVE BIM; FAMILY-MEMBER BIM; TRANSGENIC MICE; C-MYC; APOPTOTIC RESPONSES; PRE-B; LYMPHOMA; P53; SURVIVAL; PUMA
- Publisher's Version
- https://doi.org/10.1073/pnas.0401471101
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2004-04-20 12:00:00