Bim is a suppressor of Myc-induced mouse B cell leukemia

Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6164-9. doi: 10.1073/pnas.0401471101. Epub 2004 Apr 12.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Apoptosis Regulatory Proteins
  • Base Sequence
  • Bcl-2-Like Protein 11
  • Burkitt Lymphoma / genetics*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Separation
  • DNA Primers
  • Flow Cytometry
  • Genes, Tumor Suppressor*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / physiology*
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Carrier Proteins
  • DNA Primers
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Protein p53