Skip to main content

Thank you for visiting 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.

  • Letter
  • Published:

Chronic myelogenous leukemia

Coordinated inhibition of nuclear export and Bcr-Abl1 selectively targets chronic myeloid leukemia stem cells

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

Access options

Buy this article

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

Fig. 1: Inhibition of nuclear export selectively targets primitive CML cells.
Fig. 2: Meta-analysis of CML stem cell microarray studies identifies potential targets of selinexor in primitive CML cells.


  1. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N. Engl J Med. 2017;376:917–27.

    Article  CAS  Google Scholar 

  2. Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19:747–57.

    Article  CAS  Google Scholar 

  3. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Investig. 2011;121:396–409.

    Article  CAS  Google Scholar 

  4. O’Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012;12:513–26.

    Article  Google Scholar 

  5. 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;122:3034–44.

    Article  CAS  Google Scholar 

  6. 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 

  7. Khorashad JS, Eiring AM, Mason CC, Gantz KC, Bowler AD, Redwine HM, et al. shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance. Blood. 2015;125:1772–81.

    Article  CAS  Google Scholar 

  8. McWeeney SK, Pemberton LC, Loriaux MM, Vartanian K, Willis SG, Yochum G, et al. A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood. 2010;115:315–25.

    Article  CAS  Google Scholar 

  9. Heidel FH, Bullinger L, Feng Z, Wang Z, Neff TA, Stein L, et al. Genetic and pharmacologic inhibition of β-catenin targets imatinib resistant leukemia stem cells in CML. Cell Stem Cell. 2012;10:412–24.

    Article  CAS  Google Scholar 

  10. Graham SM, Vass JK, Holyoake TL, Graham GJ. Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources. Stem Cells. 2007;25:3111–20.

    Article  CAS  Google Scholar 

  11. Landberg N, von Palffy S, Askmyr M, Lilljebjorn H, Sanden C, Rissler M, et al. CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting. Haematologica. 2018;103:447–55.

    Article  CAS  Google Scholar 

  12. Singh N, Tripathi AK, Sahu DK, Mishra A, Linan M, Argente B, et al. Differential genomics and transcriptomics between tyrosine kinase inhibitor-sensitive and -resistant BCR-ABL-dependent chronic myeloid leukemia. Oncotarget. 2018;9:30385–418.

    Article  Google Scholar 

  13. Xu D, Marquis K, Pei J, Fu SC, Cagatay T, Grishin NV, et al. LocNES: a computational tool for locating classical NESs in CRM1 cargo proteins. Bioinformatics. 2015;31:1357–65.

    Article  CAS  Google Scholar 

  14. Huang W, Zhou W, Saberwal G, Konieczna I, Horvath E, Katsoulidis E, et al. Interferon consensus sequence binding protein (ICSBP) decreases β-catenin activity in myeloid cells by repressing GAS2 transcription. Mol Cell Biol. 2010;30:4575–94.

    Article  CAS  Google Scholar 

  15. Etchin J, Berezovskaya A, Conway AS, Galinsky IA, Stone RM, Baloglu E, et al. KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells. Leukemia. 2017;31:143–50.

    Article  CAS  Google Scholar 

Download references


This work was supported by a Leukemia & Lymphoma Society (LLS) Translational Research Program Award (6086-12) (MWD) and an LLS Specialized Center of Research Program Award (GCNCR0314A-UTAH) (MWD). This work was also supported by the National Institutes of Health (NIH) National Cancer Institute grant R01CA178397 (MWD and TO). CCM was funded by the pediatric cancer program, which is supported by the Intermountain Healthcare and Primary Children’s Hospital Foundations, Department of Pediatrics, Division of Pediatric Hematology/Oncology, and the University of Utah. HT was a visiting scholar from Singapore, and was supported by Research Training Fellowship from National Medical Research Council of Singapore. DY is supported by the International Award from the Lady Tata Memorial Trust following the Special Fellow Award from the LLS. We thank James Marvin, Director of the Flow Cytometry Facility at The University of Utah for assistance with experiments. The University of Utah Flow Cytometry Facility was supported by the National Cancer Institute through award 5P30CA042014-24 and the National Center for Research Resources of the NIH under award 1S10RR026802-01. We acknowledge Cell Imaging Core at the University of Utah for use of equipment and thank Michael J. Bridge, PhD for his assistance in image acquisition.

Author information

Authors and Affiliations



HT and MWD conceived the project. HT, ADP. and MWD analyzed the data. HT, ADP, TO, and MWD wrote the manuscript. CCM analyzed the microarray data. HT, ADP, LPB, AME, WLH, DY, and AS performed experiments. SS provided critical reagents. MWD provided clinical information and research materials. PMC prepared the patient samples. ADP, CCM, and TO critically reviewed the manuscript.

Corresponding author

Correspondence to Michael W. Deininger.

Ethics declarations

Conflict of interest

MWD is on the advisory board and is a consultant for Incyte, Novartis and Pfizer, and serves on the advisory board for Takeda, Blueprint and Galena BioPharma. His laboratory receives research funding from Novartis and Pfizer. SS is the President and Chief Scientific Officer of Karyopharm Therapeutics.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Than, H., Pomicter, A.D., Yan, D. et al. Coordinated inhibition of nuclear export and Bcr-Abl1 selectively targets chronic myeloid leukemia stem cells. Leukemia 34, 1679–1683 (2020).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links