Open AccessTwo mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia
Author(s) -
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,
Frank Wunderlich,
Monika Ortmann,
Manuel MontesinosRongen,
Eugen Tausch,
Stephan Stilgenbauer,
Lukas P. Frenzel,
Marco Herling,
Carmen D. Herling,
Jasmin Bahlo,
Michael Hallek,
Martin Peifer,
Reinhard Buettner,
Thorsten Persigehl,
Hans Christian Reinhardt
Publication year - 2017
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/s41467-017-00210-6
Subject(s) - chronic lymphocytic leukemia , ibrutinib , medicine , cyclophosphamide , cancer research , leukemia , oncology , immunology , chemotherapy
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.