Universität zu Köln

Herriott, Ashleigh, Tudhope, Susan J., Junge, Gesa, Rodrigues, Natalie, Patterson, Miranda J., Woodhouse, Laura, Lunec, John, Hunter, Jill E., Mulligan, Evan A., Cole, Michael, Allinson, Lisa M., Wallis, Jonathan P., Marshall, Scott, Wang, Evelyn, Curtin, Nicola J. and Willmore, Elaine ORCID: 0000-0002-4762-094X (2015). PARP1 expression, activity and ex vivo sensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia. Oncotarget, 6 (41). S. 43978 - 43992. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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/10(6) cells) compared to that seen in healthy volunteer lymphocytes (2451 - 7519 pmol PAR/10(6) 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 CD4OL-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Herriott, Ashleigh UNSPECIFIED UNSPECIFIED UNSPECIFIED Tudhope, Susan J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Junge, Gesa UNSPECIFIED UNSPECIFIED UNSPECIFIED Rodrigues, Natalie UNSPECIFIED UNSPECIFIED UNSPECIFIED Patterson, Miranda J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Woodhouse, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Lunec, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Hunter, Jill E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mulligan, Evan A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cole, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Allinson, Lisa M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wallis, Jonathan P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marshall, Scott UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Evelyn UNSPECIFIED UNSPECIFIED UNSPECIFIED Curtin, Nicola J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Willmore, Elaine UNSPECIFIED orcid.org/0000-0002-4762-094X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-383522
DOI:	10.18632/oncotarget.6287
Journal or Publication Title:	Oncotarget
Volume:	6
Number:	41
Page Range:	S. 43978 - 43992
Date:	2015
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-REPAIR; POLY(ADP-RIBOSE) POLYMERASE; MESSENGER-RNA; IN-VITRO; CELLS; CYTOTOXICITY; FLUDARABINE; APOPTOSIS; SURVIVAL; KINASE Multiple languages Oncology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38352