PARP1 expression, activity and ex vivo sensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia
Metrics: PDF 1067 views | HTML 1048 views | ?
Ashleigh Herriott1, Susan J. Tudhope1, Gesa Junge1, Natalie Rodrigues2, Miranda J. Patterson1, Laura Woodhouse1, John Lunec1, Jill E. Hunter3, Evan A. Mulligan1, Michael Cole1, Lisa M. Allinson4, Jonathan P. Wallis5, Scott Marshall6, Evelyn Wang7, Nicola J. Curtin1 and Elaine Willmore1
1 Newcastle Cancer Centre at the Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK
2 Laboratory of Lymphocyte Signaling and Oncoproteome, University Hospital of Cologne, Cologne, Germany
3 Institute of Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle-upon-Tyne, UK
4 Institute of Medical and Biological Engineering, University of Leeds, Leeds, UK
5 Department of Haematology, Freeman Hospital, Newcastle upon Tyne, UK.
6 Department of Haematology, City Hospitals Sunderland NHS Trust, Sunderland, UK
7 Biomarin Pharmaceutical Inc., Novato, California, USA
Nicola J. Curtin, email:
Keywords: PARP, CLL, talazoparib, DNA repair, ATM
Received: August 07, 2015 Accepted: October 10, 2015 Published: November 02, 2015
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.