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

<jats:p> 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 Eμ- <jats:italic>Myc</jats:italic> -transgenic mice, and <jats:italic>Bim</jats:italic> -mutant Eμ- <jats:italic>Myc</jats:italic> mice had increased numbers of IgM-bearing B cells. Eμ- <jats:italic>Myc</jats:italic> -expressing B lymphoid cells deficient in Bim were refractory to apoptosis induced <jats:italic>in vitro</jats:italic> 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 <jats:italic>Bim</jats:italic> accelerated Myc-induced development of tumors, particularly acute B cell leukemia. None of the primary tumors from <jats:italic>Bim</jats:italic> <jats:sup>+/-</jats:sup> Eμ- <jats:italic>Myc</jats:italic> mice displayed loss of the second allele of <jats:italic>Bim</jats:italic> . 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 <jats:italic>Bim</jats:italic> <jats:sup> + <jats:italic>/</jats:italic> + </jats:sup> Eμ- <jats:italic>Myc</jats:italic> mice, it was unaffected in most Bim-deficient tumors, indicating that Bim reduction is an effective alternative to loss of p53 function. </jats:p>