Bim is a suppressor of Myc-induced mouse B cell leukemia.
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 Emicro-Myc-transgenic mice, and Bim-mutant Emicro-Myc mice had increased numbers of IgM-bearing B cells. Emicro-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(+/-) Emicro-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(+/+) Emicro-Myc mice, it was unaffected in most Bim-deficient tumors, indicating that Bim reduction is an effective alternative to loss of p53 function.
Egle
Alexander
A
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, Victoria 3050, Australia.
Harris
Alan W
AW
Bouillet
Philippe
P
Cory
Suzanne
S
D000483:Alleles; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D002051:Burkitt Lymphoma / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002469:Cell Separation; D017931:DNA Primers; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D017931:DNA Primers; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53