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Abstract
Enforced Bcl-2 expression inhibits Myc-induced apoptosis and cooperates with 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-XL or Bcl-2 antiapoptotic protein. Myc activation suppresses Bcl-XL RNA and protein levels in cultures of primary myeloid and lymphoid progenitors, and Bcl-XL and Bcl-2 expression is inhibited by Myc in precancerous B cells from Eμ-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-XL by Myc is corrupted during Myc-induced tumorigenesis, as Bcl-2 and/or Bcl-XLlevels are markedly elevated in over one-half of all lymphomas arising in Eμ-myc transgenic mice. Bcl-2 and/or Bcl-XL 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-XL or Bcl-2 expression represents a physiological Myc-induced apoptotic pathway that is frequently bypassed during lymphomagenesis.
ACKNOWLEDGMENTS
We thank Charles Sherr and Gerard Zambetti for many helpful discussions and for critical review of the manuscript, Robert Hawley and Derek Persons for retrovirus vectors, Alan Harris and Charles Sidman for providing breeders for Eμ-myc mice, and Richard Cross for superb assistance with FACS. We also appreciate the outstanding technical support of Elsie White, Chunying Yang, and Rose Mathew.
This work was supported in part by National Institutes of Health (NIH) grants CA76379 and DK44158 (J.L.C.), CA71907 and CA56819 (M.F.R.), and DK45663 and DK40700 (D.W.); Cancer Center core grant CA-21765; and NIH postdoctoral grant CA81695 (C.M.E.) and by the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital.