Apoptosis triggered by Myc-induced suppression of Bcl-XL or Bcl-2 is bypassed during lymphomagenesis

Enforced Bcl-2 expression inhibits Myc-induced apoptosis and cooperates,vith Myc in transformation. Here we report that the synergy between Bcl-2 and Myc in transforming hematopoietic cells in fact reflects a Myc-induced pathway that selectively suppresses the expression of the Bcl-X-L or Bcl-2 antiapoptotic protein. Myc activation suppresses Bcl-X-L RNA and protein levels in cultures of primary myeloid and lymphoid progenitors, and Bcl-X-L and Bcl-2 expression is inhibited by Myc in precancerous B cells from E mu -myc transgenic mice. The suppression of bcl-X RNA levels by Myc requires de novo protein synthesis, indicating that repression is indirect. Importantly, the suppression of Bcl-2 or Bcl-X-L by Myc is corrupted during Myc-induced tumorigenesis, as Bcl-2 and/or Bcl-X-L levels are markedly elevated in over one-half of all lymphomas arising in E mu -myc transgenic mice. Bcl-2 and/or Bcl-X-L overexpression did not correlate with loss of ARF or p53 function in tumor cells, indicating that these two apoptotic pathways are inactivated independently. Therefore, the suppression of Bcl-X-L or Bcl-2 expression represents a physiological Myc-induced apoptotic pathway that is frequently bypassed during lymphomagenesis.