Knittel, Gero, Rehkaemper, Tim, Korovkina, Darya, Liedgens, Paul, Fritz, Christian, Torgovnick, Alessandro, Al-Baldawi, Yussor, Al-Maarri, Mona, Cun, Yupeng ORCID: 0000-0002-4241-8099, Fedorchenko, Oleg, Riabinska, Arina, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Wunderlich, F. Thomas, Ortmann, Monika, Montesinos-Rongen, Manuel, Tausch, Eugen, Stilgenbauer, Stephan, Frenzel, Lukas P., Herling, Marco, Herling, Carmen, Bahlo, Jasmin, Hallek, Michael, Peifer, Martin ORCID: 0000-0002-5243-5503, Buettner, Reinhard, Persigehl, Thorsten and Reinhardt, H. Christian (2017). Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat. Commun., 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Knittel, GeroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rehkaemper, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korovkina, DaryaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liedgens, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fritz, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torgovnick, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Baldawi, YussorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Maarri, MonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cun, YupengUNSPECIFIEDorcid.org/0000-0002-4241-8099UNSPECIFIED
Fedorchenko, OlegUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riabinska, ArinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleggia, FilippoUNSPECIFIEDorcid.org/0000-0003-0234-7094UNSPECIFIED
Wunderlich, F. ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortmann, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montesinos-Rongen, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tausch, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stilgenbauer, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenzel, Lukas P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herling, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herling, CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bahlo, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-224615
DOI: 10.1038/s41467-017-00210-6
Journal or Publication Title: Nat. Commun.
Volume: 8
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
IDENTIFIES RECURRENT MUTATIONS; DOUBLE-STRAND BREAKS; DNA-REPAIR PATHWAYS; HOMOLOGOUS RECOMBINATION; CELL LYMPHOMA; IN-VITRO; ATM; EXPRESSION; CLL; INHIBITORMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22461

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