Oncotarget

Research Papers:

Reevaluation of ATR signaling in primary resting chronic lymphocytic leukemia cells: evidence for pro-survival or pro-apoptotic function

Maxime Beyaert, Eliza Starczewska, Ana Cristina González Pérez, Nicolas Vanlangendonck, Pascale Saussoy, Gaëlle Tilman, Anne De Leener, Marie-Christiane Vekemans, Eric Van Den Neste and Françoise Bontemps _

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Oncotarget. 2017; 8:56906-56920. https://doi.org/10.18632/oncotarget.18144

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Abstract

Maxime Beyaert1, Eliza Starczewska1, Ana Cristina González Pérez1, Nicolas Vanlangendonck2, Pascale Saussoy3, Gaëlle Tilman4, Anne De Leener4, Marie-Christiane Vekemans2, Eric Van Den Neste1,2 and Françoise Bontemps1

1de Duve Institute, Université catholique de Louvain, B-1200 Brussels, Belgium

2Department of Hematology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, B-1200 Brussels, Belgium

3Service de Biologie clinique, Cliniques universitaires Saint-Luc, Université catholique de Louvain, B-1200 Brussels, Belgium

4Center for Human Genetic, Cliniques universitaires Saint-Luc, Université catholique de Louvain, B-1200 Brussels, Belgium

Correspondence to:

Françoise Bontemps, email: [email protected]

Keywords: ATR, CLL, fludarabine, UV-C, p53

Received: March 29, 2017    Accepted: April 24, 2017    Published: May 24, 2017

ABSTRACT

ATM, primarily activated by DNA double-strand breaks, and ATR, activated by single-stranded DNA, are master regulators of the cellular response to DNA damage. In primary chronic lymphocytic leukemia (CLL) cells, ATR signaling is considered to be switched off due to ATR downregulation. Here, we hypothesized that ATR, though expressed at low protein level, could play a role in primary resting CLL cells after genotoxic stress. By investigating the response of CLL cells to UV-C irradiation, a prototypical activator of ATR, we could detect phosphorylation of ATR at Thr-1989, a marker for ATR activation, and also observed that selective ATR inhibitors markedly decreased UV-C-induced phosphorylation of ATR targets, including H2AX and p53. Similar results were obtained with the purine analogs fludarabine and cladribine that were also shown to activate ATR and induce ATR-dependent phosphorylation of H2AX and p53. In addition, ATR inhibition was found to sensitize primary CLL cells to UV-C by decreasing DNA repair synthesis. Conversely, ATR inhibition rescued CLL cells against purine analogs by reducing expression of the pro-apoptotic genes PUMA and BAX. Collectively, our study indicates that ATR signaling can be activated in resting CLL cells and play a pro-survival or pro-apoptotic role, depending on the genotoxic context.


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