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 journalArticle

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
Publication statusPublished - Dec 28 2017

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Nieborowska-Skorska, M., Maifrede, S., Dasgupta, Y., Sullivan, K., Flis, S., Le, B. V., ... Skorski, T. (2017). Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms. Blood, 130(26), 2848-2859. https://doi.org/10.1182/blood-2017-05-784942