Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia

Gero Knittel (), Tim Rehkämper, Darya Korovkina, Paul Liedgens, Christian Fritz, Alessandro Torgovnick, Yussor Al-Baldawi, Mona Al-Maarri, Yupeng Cun, Oleg Fedorchenko, Arina Riabinska, Filippo Beleggia, Phuong-Hien Nguyen, F. Thomas Wunderlich, Monika Ortmann, Manuel Montesinos-Rongen, Eugen Tausch, Stephan Stilgenbauer, Lukas P. Frenzel, Marco Herling, Carmen Herling, Jasmin Bahlo, Michael Hallek, Martin Peifer, Reinhard Buettner, Thorsten Persigehl and H. Christian Reinhardt ()
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Gero Knittel: University Hospital of Cologne
Tim Rehkämper: University Hospital of Cologne
Darya Korovkina: University Hospital of Cologne
Paul Liedgens: University Hospital of Cologne
Christian Fritz: University Hospital of Cologne
Alessandro Torgovnick: University Hospital of Cologne
Yussor Al-Baldawi: University Hospital of Cologne
Mona Al-Maarri: Max-Planck-Institute for Metabolism Research
Yupeng Cun: University of Cologne
Oleg Fedorchenko: University Hospital of Cologne
Arina Riabinska: University Hospital of Cologne
Filippo Beleggia: University Hospital of Cologne
Phuong-Hien Nguyen: University Hospital of Cologne
F. Thomas Wunderlich: Max-Planck-Institute for Metabolism Research
Monika Ortmann: University Hospital of Cologne
Manuel Montesinos-Rongen: University Hospital of Cologne
Eugen Tausch: Ulm University
Stephan Stilgenbauer: Ulm University
Lukas P. Frenzel: University Hospital of Cologne
Marco Herling: University Hospital of Cologne
Carmen Herling: University Hospital of Cologne
Jasmin Bahlo: University Hospital of Cologne
Michael Hallek: University Hospital of Cologne
Martin Peifer: University of Cologne
Reinhard Buettner: University Hospital of Cologne
Thorsten Persigehl: University Hospital of Cologne
H. Christian Reinhardt: University Hospital of Cologne

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib. Thus, even in the era of targeted therapies, CLL with alterations in the ATM/p53 pathway remains a clinical challenge. Here we generated two mouse models of Atm- and Trp53-deficient CLL. These animals display a significantly earlier disease onset and reduced overall survival, compared to controls. We employed these models in conjunction with transcriptome analyses following cyclophosphamide treatment to reveal that Atm deficiency is associated with an exquisite and genotype-specific sensitivity against PARP inhibition. Thus, we generate two aggressive CLL models and provide a preclinical rational for the use of PARP inhibitors in ATM-affected human CLL.

Date: 2017
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DOI: 10.1038/s41467-017-00210-6

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