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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4455-4462.
Prepublished online as a Blood First Edition Paper on February 17, 2005; DOI 10.1182/blood-2004-05-1699.
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Submitted May 5, 2004
Accepted January 17, 2005
Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP
Kumudha Balakrishnan, Christine M Stellrecht, Davide Genini, Mary Ayres, William G Wierda, Michael J Keating, Lorenzo M Leoni, and Varsha Gandhi*
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Medicine and The Sam and Rose Stein Institute for Research on Aging, University of California at San Diego, La Jolla, CA, USA
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
* Corresponding author; email: vgandhi{at}mdanderson.org.
MCL-1 acts as a key survival factor for chronic lymphocytic leukemia (CLL) cells. In addition, dissipation of cellular bioenergy may impose a lethal effect on these quiescent cells. Previously, in multiple myeloma cell lines we demonstrated that halogenated adenosine (8-Cl-Ado) was phosphorylated to its triphosphate (8-Cl-ATP), which, preferentially incorporated into mRNA, and inhibited RNA synthesis by premature transcription termination. Furthermore, 8-Cl-ATP accumulation was associated with a decline in cellular bioenergy. Based on these actions, we hypothesized that 8-Cl-Ado would be ideal to target CLL lymphocytes. In the present study we demonstrate that leukemic lymphocytes incubated with 8-Cl-Ado display time and dose dependent increase in the accumulation of 8-Cl-ATP, with a parallel depletion of the endogenous ATP pool. Inhibition of global RNA synthesis resulted in a significant decline in the expression of transcripts with short half-life such as MCL-1. Consistent to this, protein expression of MCL-1 but not BCL-2 was decreased. Furthermore, 8-Cl-ATP induced programmed cell death, as suggested by caspases activation, cleavage of caspase 3 and PARP and increased DNA fragmentation. In conclusion, 8-Cl-Ado induces apoptosis in CLL lymphocytes by targeting cellular bioenergy as well as RNA transcription and translation of key survival genes such as MCL-1.
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