title: Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP.
abstract: Myeloid cell leukemia-1 (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 triphosphate (8-Cl-adenosine triphosphate [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 a short half-life such as MCL1. Consistent to this, protein expression of MCL-1 but not B-cell lymphoma-2 (BCL-2) was decreased. Furthermore, 8-Cl-ATP induced programmed cell death, as suggested by caspases activation, cleavage of caspase 3, and PARP (poly-adenosine diphosphate [ADP]-ribose polymerase), 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 MCL1.
authors.affiliation: Department of Experimental Therapeutics, Unit 71, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.forename: Christine M
authors.initials: CM
authors.lastname: Stellrecht
authors.forename: Davide
authors.initials: D
authors.lastname: Genini
authors.forename: Mary
authors.initials: M
authors.lastname: Ayres
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Lorenzo M
authors.initials: LM
authors.lastname: Leoni
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C465859:8-chloro-ATP; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D000255:Adenosine Triphosphate
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