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Blood. 2017 Dec 28;130(26):2848-2859. doi: 10.1182/blood-2017-05-784942. Epub 2017 Oct 17.

Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms.

Author information

1
Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
2
Department of Pharmacology, National Medicines Institute, Warsaw, Poland.
3
Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland.
4
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
5
Department of Biomedicine, University Hospital Basel/University of Basel, Basel, Switzerland.
6
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
7
Department of Clinical Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
8
School of Medicine, University of Utah, Salt Lake City, UT.
9
Division of Hematology, Department of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, MD; and.
10
Cambridge Institute for Medical Research.
11
Wellcome-Medical Research Council Cambridge Stem Cell Institute, and.
12
Department of Haematology, University of Cambridge, Cambridge, United Kingdom; and.
13
Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.

Abstract

Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L), or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time, primary MPN cell samples from individual patients displayed a high degree of variability in sensitivity to these drugs. Ruxolitinib inhibited 2 major DSB repair mechanisms, BRCA-mediated homologous recombination and DNA-dependent protein kinase-mediated nonhomologous end-joining, and, when combined with olaparib, caused abundant accumulation of toxic DSBs resulting in enhanced elimination of MPN primary cells, including the disease-initiating cells from the majority of patients. Moreover, the combination of BMN673, ruxolitinib, and hydroxyurea was highly effective in vivo against JAK2(V617F)+ murine MPN-like disease and also against JAK2(V617F)+, CALR(del52)+, and MPL(W515L)+ primary MPN xenografts. In conclusion, we postulate that ruxolitinib-induced deficiencies in DSB repair pathways sensitized MPN cells to synthetic lethality triggered by PARP inhibitors.

PMID:
29042365
PMCID:
PMC5746670
[Available on 2018-12-28]
DOI:
10.1182/blood-2017-05-784942
[Indexed for MEDLINE]

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