دورية أكاديمية
Nuclear-Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis.
العنوان: | Nuclear-Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis. |
---|---|
المؤلفون: | 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. |
المصدر: | 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. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
مواضيع طبية MeSH: | Cell Nucleus/*metabolism , Cytoplasm/*metabolism , Primary Myelofibrosis/*metabolism, Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Biological Transport/drug effects ; Biomarkers ; Cell Line, Tumor ; Cell Nucleus/drug effects ; Computational Biology/methods ; Cytoplasm/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Gene Expression Profiling ; Gene Knockdown Techniques ; Humans ; Janus Kinases/genetics ; Janus Kinases/metabolism ; Mice ; Molecular Targeted Therapy ; Mutation ; Myeloproliferative Disorders/etiology ; Myeloproliferative Disorders/metabolism ; Myeloproliferative Disorders/pathology ; Primary Myelofibrosis/drug therapy ; Primary Myelofibrosis/etiology ; STAT Transcription Factors/metabolism ; Transcriptome |
مستخلص: | 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.) |
References: | Lancet. 2005 Mar 19-25;365(9464):1054-61. (PMID: 15781101) Leukemia. 2016 Aug;30(8):1701-7. (PMID: 27211272) Blood. 2015 Mar 12;125(11):1772-81. (PMID: 25573989) Sci Rep. 2015 Sep 24;5:14391. (PMID: 26399741) Blood. 2010 Jun 24;115(25):5232-40. (PMID: 20385788) Leukemia. 2016 Dec;30(12):2364-2372. (PMID: 27323910) Haematologica. 2005 Aug;90(8):1128-32. (PMID: 16079113) Blood. 2017 Jul 13;130(2):115-125. (PMID: 28500170) Blood Cancer J. 2014 Dec 12;4:e268. (PMID: 25501025) Exp Hematol. 2015 Jul;43(7):537-45.e1-11. (PMID: 25912019) N Engl J Med. 2009 May 28;360(22):2289-301. (PMID: 19474426) PLoS Med. 2006 Jul;3(7):e270. (PMID: 16834459) J Clin Oncol. 2005 Nov 20;23(33):8520-30. (PMID: 16293880) N Engl J Med. 2012 Mar 1;366(9):787-98. (PMID: 22375970) Clin Cancer Res. 2016 Apr 1;22(7):1663-73. (PMID: 26603256) Exp Hematol Oncol. 2015 Mar 01;4:7. (PMID: 25745591) Blood Cancer J. 2018 Feb 9;8(2):15. (PMID: 29426921) Blood. 2013 Aug 22;122(8):1395-8. (PMID: 23838352) Br J Haematol. 2013 Apr;161(1):117-27. (PMID: 23373539) BMC Cancer. 2016 Feb 27;16:167. (PMID: 26922064) Oncotarget. 2017 Jan 31;8(5):7521-7532. (PMID: 27893412) Br J Cancer. 2014 Jul 15;111(2):281-91. (PMID: 24946002) PLoS One. 2014 Mar 11;9(3):e90299. (PMID: 24618579) J Clin Oncol. 2017 Dec 1;35(34):3844-3850. (PMID: 28930494) Nature. 2012 Sep 6;489(7414):155-9. (PMID: 22820254) N Engl J Med. 2012 Mar 1;366(9):799-807. (PMID: 22375971) J Hematol Oncol. 2017 Feb 22;10(1):55. (PMID: 28228106) Cancer Cell. 2018 Jan 8;33(1):29-43.e7. (PMID: 29249691) Blood. 2011 Jul 28;118(4):899-902. (PMID: 21622644) Cancer Cell. 2005 Apr;7(4):387-97. (PMID: 15837627) Leukemia. 2008 Aug;22(8):1636-8. (PMID: 18305559) Leukemia. 2017 Jan;31(1):143-150. (PMID: 27211268) Blood. 2014 Aug 14;124(7):1183-91. (PMID: 24963042) Gastroenterology. 2013 Feb;144(2):447-56. (PMID: 23089203) Cancer Res. 2006 Dec 1;66(23):11156-65. (PMID: 17145859) Curr Cancer Drug Targets. 2015;15(7):575-92. (PMID: 26324128) Am J Hematol. 2010 Aug;85(8):616-9. (PMID: 20540156) Nat Struct Mol Biol. 2009 May;16(5):558-60. (PMID: 19339972) N Engl J Med. 2013 Dec 19;369(25):2391-2405. (PMID: 24325359) Leukemia. 2015 Jan;29(1):20-6. (PMID: 25151955) Oncotarget. 2014 Aug 15;5(15):6102-12. (PMID: 25026284) Cancer Discov. 2014 May;4(5):527-37. (PMID: 24743138) Leukemia. 2010 Jul;24(7):1302-9. (PMID: 20508616) Leukemia. 2011 Jul;25(7):1219-20. (PMID: 21519343) Lancet Haematol. 2017 May;4(5):e225-e236. (PMID: 28336242) Cancer Chemother Pharmacol. 2014 Sep;74(3):487-95. (PMID: 25030088) Pharmacol Rev. 1995 Jun;47(2):331-85. (PMID: 7568331) N Engl J Med. 2013 Dec 19;369(25):2379-90. (PMID: 24325356) Nature. 2009 Apr 30;458(7242):1136-41. (PMID: 19339969) Cancer Cell. 2015 Jul 13;28(1):15-28. (PMID: 26175413) Clin Cancer Res. 2016 Mar 1;22(5):1037-47. (PMID: 26933174) Blood. 2015 Sep 24;126(13):1551-4. (PMID: 26228487) Nat Genet. 2010 Aug;42(8):722-6. (PMID: 20601953) JAMA Oncol. 2015 Aug;1(5):643-51. (PMID: 26181658) Leukemia. 2009 Nov;23(11):2183-6. (PMID: 19609284) Leukemia. 2014 Jul;28(7):1472-7. (PMID: 24402162) N Engl J Med. 2005 Apr 28;352(17):1779-90. (PMID: 15858187) |
معلومات مُعتمدة: | P30 CA042014 United States CA NCI NIH HHS; R01 CA178397 United States CA NCI NIH HHS; S10 RR026802 United States RR NCRR NIH HHS |
المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Biomarkers) 0 (STAT Transcription Factors) EC 2.7.10.2 (Janus Kinases) |
تواريخ الأحداث: | Date Created: 20181220 Date Completed: 20200511 Latest Revision: 20200511 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC6445677 |
DOI: | 10.1158/1078-0432.CCR-18-0959 |
PMID: | 30563936 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1557-3265 |
---|---|
DOI: | 10.1158/1078-0432.CCR-18-0959 |