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Yan, Dongqing; Pomicter, Anthony D; Tantravahi, Srinivas; Mason, Clinton C; Senina, Anna V; Ahmann, Jonathan M; Wang, Qiang; Than, Hein; Patel, Ami B; Heaton, William L; Eiring, Anna M; Clair, Phillip M; Gantz, Kevin C; Redwine, Hannah M; Swierczek, Sabina I; Halverson, Brayden J; Baloglu, Erkan; Shacham, Sharon; Khorashad, Jamshid S; Kelley, Todd W; Salama, Mohamed E; Miles, Rodney R; Boucher, Kenneth M; Prchal, Josef T; O'Hare, Thomas; Deininger, Michael W
Clinical cancer research, 04/2019, Letnik: 25, Številka: 7Journal Article
Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in , or is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis. A short hairpin RNA library screening was performed on JAK2 -mutant HEL cells. Nuclear-cytoplasmic transport (NCT) genes including and were among top candidates. JAK2 -mutant cell lines, human primary myelofibrosis CD34 cells, and a retroviral JAK2 -driven myeloproliferative neoplasms mouse model were used to determine the effects of inhibiting NCT with selective inhibitors of nuclear export compounds KPT-330 (selinexor) or KPT-8602 (eltanexor). JAK2 -mutant HEL, SET-2, and HEL cells resistant to JAK inhibition are exquisitely sensitive to RAN knockdown or pharmacologic inhibition by KPT-330 or KPT-8602. Inhibition of NCT selectively decreased viable cells and colony formation by myelofibrosis compared with cord blood CD34 cells and enhanced ruxolitinib-mediated growth inhibition and apoptosis, both in newly diagnosed and ruxolitinib-exposed myelofibrosis cells. Inhibition of NCT in myelofibrosis CD34 cells led to nuclear accumulation of p53. KPT-330 in combination with ruxolitinib-normalized white blood cells, hematocrit, spleen size, and architecture, and selectively reduced JAK2 -mutant cells . Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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