title: PARP1 expression, activity and ex vivo sensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia.
abstract: In chronic lymphocytic leukemia (CLL), mutation and loss of p53 and ATM abrogate DNA damage signalling and predict poorer response and shorter survival. We hypothesised that poly (ADP-ribose) polymerase (PARP) activity, which is crucial for repair of DNA breaks induced by oxidative stress or chemotherapy, may be an additional predictive biomarker and a target for therapy with PARP inhibitors.We measured PARP activity in 109 patient-derived CLL samples, which varied widely (192 - 190052 pmol PAR/10⁶ cells) compared to that seen in healthy volunteer lymphocytes (2451 - 7519 pmol PAR/10⁶ cells). PARP activity was associated with PARP1 protein expression and endogenous PAR levels. PARP activity was not associated with p53 or ATM loss, Binet stage, IGHV mutational status or survival, but correlated with Bcl-2 and Rel A (an NF-kB subunit). Levels of 8-hydroxy-2'-deoxyguanosine in DNA (a marker of oxidative damage) were not associated with PAR levels or PARP activity. The potent PARP inhibitor, talazoparib (BMN 673), inhibited CD40L-stimulated proliferation of CLL cells at nM concentrations, independently of Binet stage or p53/ATM function.PARP activity is highly variable in CLL and correlates with stress-induced proteins. Proliferating CLL cells (including those with p53 or ATM loss) are highly sensitive to the PARP inhibitor talazoparib.
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Herriott
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Tudhope
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Gesa
authors.initials: G
authors.lastname: Junge
authors.affiliation: Laboratory of Lymphocyte Signaling and Oncoproteome, University Hospital of Cologne, Cologne, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Rodrigues
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Patterson
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Woodhouse
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: John
authors.initials: J
authors.lastname: Lunec
authors.affiliation: Institute of Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Hunter
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Mulligan
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Cole
authors.affiliation: Institute of Medical and Biological Engineering, University of Leeds, Leeds, UK.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Allinson
authors.affiliation: Department of Haematology, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Wallis
authors.affiliation: Department of Haematology, City Hospitals Sunderland NHS Trust, Sunderland, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Marshall
authors.affiliation: Biomarin Pharmaceutical Inc., Novato, California, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Wang
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Willmore
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D014408:Biomarkers, Tumor; D004249:DNA Damage / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010793:Phthalazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D012372:ROC Curve; D012680:Sensitivity and Specificity
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C586365:talazoparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: ATM; CLL; DNA repair; PARP; talazoparib