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.
Highlights
B-cell chronic lymphocytic leukaemia (CLL) patients have a variable disease but the onset of molecular profiling has revolutionised our understanding of CLL, and identified recurrent mutations and novel targets that may be exploited therapeutically
poly (ADP-ribose) polymerase (PARP) activity was less variable in PBMCs from healthy volunteers (HV), and this was from a small cohort (n = 8) it was within the range seen in a separate HV cohort (n = 56) in our previous study (10 - 2,190 pmol PAR/106cells; [23])
To understand the variation in PARP activity observed, we measured Poly(ADP-ribose) polymerase-1 (PARP1) protein levels and discovered that, there was a significant correlation between protein levels and activity, the strength of the correlation was weak as observed previously [23]
Summary
B-cell chronic lymphocytic leukaemia (CLL) patients have a variable disease but the onset of molecular profiling has revolutionised our understanding of CLL, and identified recurrent mutations and novel targets that may be exploited therapeutically. Current treatment protocols have improved response rates for many patients [1] and newer approaches targeting B-cell receptor (BCR) signalling show great promise in clinical trials [2]. Despite these advances, CLL remains incurable, and since CLL patients are predominantly elderly, they cannot tolerate www.impactjournals.com/oncotarget aggressive therapies. Cytogenetic abnormalities including mutation and loss of p53 and ataxia telangiectasia mutated kinase (ATM) (del(17p) and del(11q) respectively) confer chemoresistance and are associated with poorer response and shorter overall survival [3, 4] Both ATM and p53 signal DNA double-strand breaks (DSB) with ATM promoting their high-fidelity repair by homologous recombination repair (HRR). The mechanism of action of the BTK inhibitors is p53-independent, underlying genomic instability in patients with p53 and ATM loss can result in acquired mutations in the kinase, resulting in drug resistance [5]
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