Nuclear-Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis.

Autor:	Yan D; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Pomicter AD; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Tantravahi S; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah.; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah., Mason CC; Department of Pediatrics, The University of Utah, Salt Lake City, Utah., Senina AV; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Ahmann JM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Wang Q; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah.; Department of Hematology, Nanfang Hospital, Southern Medical University., Than H; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah.; Department of Haematology, Singapore General Hospital, Singapore., Patel AB; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah.; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah., Heaton WL; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Eiring AM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Clair PM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Gantz KC; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Redwine HM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Swierczek SI; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah., Halverson BJ; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Baloglu E; Karyopharm Therapeutics, Inc, Newton, Massachusetts., Shacham S; Karyopharm Therapeutics, Inc, Newton, Massachusetts., Khorashad JS; Department of Cellular Pathology, Hammersmith Hospital, Imperial College Health Care NHS Trust, London, United Kingdom., Kelley TW; Department of Pathology, The University of Utah, Salt Lake City, Utah., Salama ME; Department of Pathology, The University of Utah, Salt Lake City, Utah., Miles RR; Department of Pathology, The University of Utah, Salt Lake City, Utah., Boucher KM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah., Prchal JT; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah., O'Hare T; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah.; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah., Deininger MW; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah. michael.deininger@hci.utah.edu.; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Apr 01; Vol. 25 (7), pp. 2323-2335. Date of Electronic Publication: 2018 Dec 18.
DOI:	10.1158/1078-0432.CCR-18-0959
Abstrakt:	Purpose: 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 JAK2, CALR , or MPL 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. Experimental Design: A short hairpin RNA library screening was performed on JAK2 V617F -mutant HEL cells. Nuclear-cytoplasmic transport (NCT) genes including RAN and RANBP2 were among top candidates. JAK2 V617F -mutant cell lines, human primary myelofibrosis CD34 + cells, and a retroviral JAK2 V617F -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). Results: JAK2 V617F -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 V617F -mutant cells in vivo . Conclusions: Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis. (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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