A subset of chronic lymphocytic leukemia patients display reduced levels of PARP1 expression coupled with a defective irradiation-induced apoptosis.

Abstract : Chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by defects in the DNA damage response and apoptosis. Among the factors involved in these pathways, we focused on the enzyme poly(ADP-ribose) polymerase 1 (PARP1) and on its substrate Che-1 by evaluating their basal expression and functional changes upon irradiation (IR). Microarray experiments were performed on 98 untreated CLL cases. Next, freshly isolated primary cells from 21 untreated patients were analyzed for in vitro response to irradiation through Western blot, PARP activity assay, Annexin-V analysis, and PARP1 basal expression by quantitative polymerase chain reaction. Microarray analysis showed that PARP1 and CHE1 were constitutively expressed in CLL and had a high degree of correlation with each other and with TP53. PARP1 and TP53 downmodulation was associated with worse clinical outcomes, especially in TP53-mutated cases. Next, CLL samples from 21 untreated patients were classified as responders and nonresponders based on IR-induced PARP1 cleavage. Notably, while responder samples were characterized by Che-1 and p53 induction at 8 hours and reduction at 24 hours post-IR, nonresponders included both samples with p53 dysfunctions and cases with a normal IR-induced Che-1 and/or p53 response. Finally, we observed that PARP1 was downregulated in nonresponder vs responder samples and that its basal expression was positively correlated with PARP1 cleavage after IR. In conclusion, we showed that reduced expression of PARP1 is associated with an impairment of CLL responsiveness to cell death.
Document type :
Journal articles
Complete list of metadatas

Cited literature [47 references]  Display  Hide  Download

https://hal-riip.archives-ouvertes.fr/pasteur-00976881
Contributor : Istituto Pasteur Fondazione Cenci Bolognetti <>
Submitted on : Thursday, April 10, 2014 - 2:40:58 PM
Last modification on : Monday, October 8, 2018 - 5:44:07 PM
Long-term archiving on : Monday, April 10, 2017 - 11:49:12 AM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Maria Giulia Bacalini, Simona Tavolaro, Nadia Peragine, Marilisa Marinelli, Simona Santangelo, et al.. A subset of chronic lymphocytic leukemia patients display reduced levels of PARP1 expression coupled with a defective irradiation-induced apoptosis.. Experimental Hematology, Elsevier, 2012, 40 (3), pp.197-206.e1. ⟨10.1016/j.exphem.2011.11.005⟩. ⟨pasteur-00976881⟩

Share

Metrics

Record views

81