Journal
BLOOD
Volume 130, Issue 26, Pages 2848-2859Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-05-784942
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Funding
- Leukemia & Lymphoma Society Quest-for-Cure [0860-15]
- National Institutes of Health National Cancer Institute [CA134458]
- Narodowe Centrum Nauki [2013/11/B/NZ7/02248]
- European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie [665735]
- Polish Ministry of Science and Higher Education for the implementation of international projects
- Cambridge National Institute for Health Research Biomedical Research Centre
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute
- Medical Research Council [MC_PC_12009] Funding Source: researchfish
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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.
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