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Molecular and Cellular Biology, August 2001, p. 5063-5070, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5063-5070.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Apoptosis Triggered by Myc-Induced Suppression of Bcl-XL or Bcl-2 Is Bypassed during Lymphomagenesis

Christine M. Eischen,1 David Woo,2 Martine F. Roussel,3,4 and John L. Cleveland1,3,*

Department of Biochemistry1 and Department of Tumor Cell Biology,4 St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Division of Nephrology, Department of Medicine, University of California, Los Angeles, Los Angeles, California 900952; and Department of Biochemistry, University of Tennessee, Memphis, Tennessee 381633

Received 2 November 2000/Returned for modification 19 December 2000/Accepted 1 May 2001

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-XL levels 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.

* Corresponding author. Mailing address: St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-2398. Fax: (901) 525-8025. E-mail: john.cleveland{at}stjude.org.

Molecular and Cellular Biology, August 2001, p. 5063-5070, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5063-5070.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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