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

Margaret Nieborowska-Skorska, Silvia Maifrede, Yashodhara Dasgupta, Katherine Sullivan, Sylwia Flis, Bac Viet Le, Martyna Solecka, Elizaveta A. Belyaeva, Lucia Kubovcakova, Morgan Nawrocki, Martin Kirschner, Huaqing Zhao, Josef T. Prchal, Katarzyna Piwocka, Alison R. Moliterno, Mariusz Wasik, Steffen Koschmieder, Tony R. Green, Radek C. Skoda, Tomasz Skorski

Research output: Contribution to journalArticlepeer-review

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, primaryMPNcell 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 MPNlike 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.

Original languageEnglish (US)
Pages (from-to)2848-2859
Number of pages12
JournalBlood
Volume130
Issue number26
DOIs
StatePublished - Dec 28 2017

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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