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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2513-2519.
Prepublished online as a Blood First Edition Paper on June 21, 2005; DOI 10.1182/blood-2005-04-1678.
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Submitted April 26, 2005
Accepted June 2, 2005
Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death
Rong Chen, Michael J Keating, Varsha Gandhi, and William Plunkett*
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
* Corresponding author; email: wplunket{at}mdanderson.org.
Flavopiridol is active against CLL cells in vitro and in the treatment of advanced stage disease, but the mechanisms of these actions remain unclear. Originally developed as a general cyclin-dependent kinase inhibitor, flavopiridol is a potent transcriptional suppressor through the inhibition of P-TEFb (CDK9/cyclin T). P-TEFb phosphorylates the C-terminal domain (CTD) of RNA polymerase II to promote transcriptional elongation. Because most CLL cells are not actively cycling, and their viability is dependent upon the continuous expression of anti-apoptotic proteins, we hypothesized that flavopiridol induces apoptosis in CLL cells through the transcriptional down-regulation of such proteins. This study demonstrated that flavopiridol inhibited the phosphorylation of the CTD of RNA polymerase II in primary CLL cells and reduced RNA synthesis. This was associated with a decline of the transcripts and the levels of short-lived anti-apoptotic proteins such as Mcl-1 and XIAP, and resulted in the induction of apoptosis. The Bcl-2 protein level remained stable, although its mRNA was consistently reduced, suggesting that the outcome of transcription inhibition by flavopiridol is governed by the intrinsic stability of the individual transcripts and proteins. The dependence of CLL cell survival on short-lived oncoproteins may provide the biochemical basis for the therapeutic index in response to flavopiridol.
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