Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Molecular targets for therapy

Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice

Leukemia volume 30, page 0 (2016)Cite this article

Subjects

Abstract

Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Estey EH . Acute myeloid leukemia: 2014 update on risk-stratification and management. Am J Hematol 2014; 89: 1063–1081.

    Article  CAS  Google Scholar 

  2. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

    Article  CAS  Google Scholar 

  3. Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.

    Article  CAS  Google Scholar 

  4. Hope KJ, Jin L, Dick JE . Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 2004; 5: 738–743.

    Article  CAS  Google Scholar 

  5. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–648.

    Article  CAS  Google Scholar 

  6. Gilliland DG, Jordan CT, Felix CA . The molecular basis of leukemia. Hematology Am Soc Hematol Educ Program 2004, 80–97.

    Article  Google Scholar 

  7. Fornerod M, Ohno M, Yoshida M, Mattaj IW . CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 1997; 90: 1051–1060.

    Article  CAS  Google Scholar 

  8. Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M . CRM1 is responsible for intracellular transport meditted by the nuclear export signal. Nature 1997; 390: 308–311.

    Article  CAS  Google Scholar 

  9. Ossareh-Nazari B, Bachelerie F, Dargemont C . Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science 1997; 278: 141–144.

    Article  CAS  Google Scholar 

  10. Turner JG, Dawson J, Sullivan DM . Nuclear export of proteins and drug resistance in cancer. Biochem Pharmacol 2012; 83: 1021–1032.

    Article  CAS  Google Scholar 

  11. Stade K, Ford CS, Guthrie C, Weis K . Exportin 1 (Crm1p) is an essential nuclear export factor. Cell 1997; 90: 1041–1050.

    Article  CAS  Google Scholar 

  12. Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL . eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 2006; 175: 415–426.

    Article  CAS  Google Scholar 

  13. Xu D, Farmer A, Chook YM . Recognition of nuclear targeting signals by Karyopherin-beta proteins. Curr Opin Struct Biol 2010; 20: 782–790.

    Article  CAS  Google Scholar 

  14. Dong X, Biswas A, Chook YM . Structural basis of assembly and disassembly of the CRM1 nuclear export complex. Nat Struct Mol Biol 2009; 16: 558–560.

    Article  CAS  Google Scholar 

  15. Dong X, Biswas A, Suel KE, Jackson LK, Martinez R, Gu H et al. Structural basis for leucine-rich nuclear export signal recognition by CRM1. Nature 2009; 458: 1136–1141.

    Article  CAS  Google Scholar 

  16. Guttler T, Gorlich D . Ran-dependent nuclear export mediators: a structural perspective. EMBO J 2011; 30: 3457–3474.

    Article  Google Scholar 

  17. Hutten S, Kehlenbach RH . CRM1-mediated nuclear export: to the pore and beyond. Trends Cell Biol 2007; 17: 193–201.

    Article  CAS  Google Scholar 

  18. Koyama M, Matsuura Y . An allosteric mechanism to displace nuclear export cargo from CRM1 and RanGTP by RanBP1. EMBO J 2010; 29: 2002–2013.

    Article  CAS  Google Scholar 

  19. Xu D, Farmer A, Collett G, Grishin NV, Chook YM . Sequence and structural analyses of nuclear export signals in the NESdb database. Mol Biol Cell 2012; 23: 3677–3693.

    Article  CAS  Google Scholar 

  20. Xu D, Grishin NV, Chook YM . NESdb: a database of NES-containing CRM1 cargos. Mol Biol Cell 2012; 23: 3673–3676.

    Article  CAS  Google Scholar 

  21. Kojima K, Kornblau SM, Ruvolo V, Dilip A, Duvvuri S, Davis RE et al. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood 2013; 121: 4166–4174.

    Article  CAS  Google Scholar 

  22. Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y et al. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood 2012; 120: 4621–4634.

    Article  CAS  Google Scholar 

  23. Huang WY, Yue L, Qiu WS, Wang LW, Zhou XH, Sun YJ . Prognostic value of CRM1 in pancreas cancer. Clin Invest Med 2009; 32: E315.

    Article  Google Scholar 

  24. Inoue H, Kauffman M, Shacham S, Landesman Y, Yang J, Evans CP et al. CRM1 blockade by selective inhibitors of nuclear export attenuates kidney cancer growth. J Urol 2013; 189: 2317–2326.

    Article  CAS  Google Scholar 

  25. Shen A, Wang Y, Zhao Y, Zou L, Sun L, Cheng C . Expression of CRM1 in human gliomas and its significance in p27 expression and clinical prognosis. Neurosurgery 2009; 65: 153–159, discussion 159–160.

    Article  Google Scholar 

  26. Walker CJ, Oaks JJ, Santhanam R, Neviani P, Harb JG, Ferenchak G et al. Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood 2013; 122: 3034–3044.

    Article  CAS  Google Scholar 

  27. Yao Y, Dong Y, Lin F, Zhao H, Shen Z, Chen P et al. The expression of CRM1 is associated with prognosis in human osteosarcoma. Oncol Rep 2009; 21: 229–235.

    CAS  Google Scholar 

  28. Etchin J, Sanda T, Mansour MR, Kentsis A, Montero J, Le BT et al. KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia. Br J Haematol 2013; 161: 117–127.

    Article  CAS  Google Scholar 

  29. Kalid O, Toledo Warshaviak D, Shechter S, Sherman W, Shacham S . Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors. J Comput Aided Mol Des 2012; 26: 1217–1228.

    Article  CAS  Google Scholar 

  30. Etchin J, Sun Q, Kentsis A, Farmer A, Zhang ZC, Sanda T et al. Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. Leukemia 2013; 27: 66–74.

    Article  CAS  Google Scholar 

  31. Savona M, Garzon R, de Nully Brown P, Yee K, Lancet JE, Gutierrez M et al. Phase I trial of selinexor (KPT-330), a first-in-class oral selective inhibitor of nuclear export (SINE) in patients (pts) with advanced acute myelogenous leukemia (AML). Blood 2013; 122.

  32. Ranganathan P, Yu X, Na C, Santhanam R, Shacham S, Kauffman M et al. Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood 2012; 120: 1765–1773.

    Article  CAS  Google Scholar 

  33. Schmidt J, Braggio E, Kortuem KM, Egan JB, Zhu YX, Xin CS et al. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia 2013; 27: 2357–2365.

    Article  CAS  Google Scholar 

  34. Tai YT, Landesman Y, Acharya C, Calle Y, Zhong MY, Cea M et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia 2014; 28: 155–165.

    Article  CAS  Google Scholar 

  35. Sarry JE, Murphy K, Perry R, Sanchez PV, Secreto A, Keefer C et al. Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rgammac-deficient mice. J Clin Invest 2011; 121: 384–395.

    Article  CAS  Google Scholar 

  36. Ryan J, Letai A . BH3 profiling in whole cells by fluorimeter or FACS. Methods 2013; 61: 156–164.

    Article  CAS  Google Scholar 

  37. Ryan JA, Brunelle JK, Letai A . Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proc Natl Acad Sci USA 2010; 107: 12895–12900.

    Article  CAS  Google Scholar 

  38. Hu Y, Smyth GK . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods 2009; 347: 70–78.

    Article  CAS  Google Scholar 

  39. Borrow J, Stanton VP Jr, Andresen JM, Becher R, Behm FG, Chaganti RS et al. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet 1996; 14: 33–41.

    Article  CAS  Google Scholar 

  40. Yosef Landesman WS, Jean-Richard S-M, Trinayan K, Louis P, Vincent S, Sharon S et al. Abstract 3775: Pharmacokinetic (PK)/pharmacodynamic (PD) and efficacy relationship of selective inhibitors of nuclear export (KPT-SINE). Cancer Res 2012; 72: 3775.

    Article  Google Scholar 

  41. Del Gaizo Moore V, Letai A . BH3 profiling—measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. Cancer Lett 2013; 332: 202–205.

    Article  CAS  Google Scholar 

  42. Montero J, Sarosiek KA, DeAngelo JD, Maertens O, Ryan J, Ercan D et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 2015; 160: 977–989.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients for their cooperation in providing bone marrow samples for this study; Ilene Galinsky for providing the patient samples used to generate mouse PDX models of human AML; Nancy Kohl, Paul Kirschmeier and Prafulla Gokhale for assistance in guiding in vivo studies at the Lurie Family Imaging Center; John Gilbert for his editorial review and critical reading of the manuscript; and John Daley and the flow cytometry team for their valuable advice. This research was supported by William Lawrence and Blanche Hughes Foundation (to ATL), Leukemia and Lymphoma Society’s Translational research grant (to ATL), Alex’s Lemonade Stand Foundation’s Young Research Investigator grant (to JE), Luck2Tuck Foundation (to JE), Claudia Adams Barr Innovative Basic Science Research grant (to MRM) and Lady Tata Memorial Trust (to CELN).

Author contributions

JE designed and performed experiments, analyzed data and wrote the manuscript. BTL and AB performed experiments and analyzed data. ALC, CR and AB helped design and perform in vivo mouse studies. AK, MRM, CELN and SA participated in experimental design and data analysis. SS and MK designed the KPT-330 compound and participated in the design of in vivo mouse studies. IAG and RMS provided AML patient samples and helped to analyze the data. SJR interpreted the hematopathology. BK, YL, WCC, JCYW and ALK designed experiments and analyzed the data. JM and AL designed and performed BH3 profiling experiments and analyzed data. ATL guided the research, analyzed the results and wrote the paper.

Author information

Author notes

  1. A Berezovskaya and B T Le: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Oncology, and Division of Hematology/Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA

    J Etchin, A Berezovskaya, B T Le, A L Christie, A S Conway, C Reed, M R Mansour, C E L Ng & A T Look

  2. Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA

    J Etchin & A T Look

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA

    J Montero, S Adamia, I A Galinsky, R M Stone & A Letai

  4. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    A Kentsis

  5. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    W C Chen & J C Y Wang

  6. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    W C Chen & J C Y Wang

  7. Department of Haematology, UCL Cancer Institute, University College London, London, UK

    M R Mansour

  8. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    S J Rodig

  9. Karyopharm Therapeutics, Natick, MA, USA

    B Klebanov, Y Landesman, M Kauffman & S Shacham

  10. Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, NY, USA

    A L Kung

Authors
  1. J Etchin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Montero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Berezovskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B T Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Kentsis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A L Christie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A S Conway
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W C Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M R Mansour
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C E L Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S Adamia
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S J Rodig
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. I A Galinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. R M Stone
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. B Klebanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Y Landesman
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. M Kauffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. S Shacham
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. A L Kung
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. J C Y Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. A Letai
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. A T Look
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A T Look.

Ethics declarations

Competing interests

BK, SS, MK and YL are employees of Karyopharm Therapeutics Incorporated and receive compensation and hold equity in the company. The other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Etchin, J., Montero, J., Berezovskaya, A. et al. Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice. Leukemia 30, 0 (2016). https://doi.org/10.1038/leu.2015.194

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.194

This article is cited by

Search

Advanced search

Quick links