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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 and Tomasz Skorski

Key points

  • Ruxolitinib caused DNA repair defects and sensitized MPN stem and progenitor cells to PARP inhibitors.

  • Quiescent and proliferating MPN cells were eliminated by ruxolitinib and olaparib +/- hydroxyurea.

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 the sensitivity to these drugs. Ruxolitinib inhibited two major DSB repair mechanisms, BRCA-mediated homologous recombination and DNA-PK –mediated non-homologous 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)-positive murine MPN-like disease and also against JAK2(V617F), CALR(del52), and MPL(W515L)-positive 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.

  • Submitted May 15, 2017.
  • Accepted October 12, 2017.