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Chronic myelogenous leukemia

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

Leukemia volume 34, pages 1679–1683 (2020)Cite this article

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Patients with chronic phase CML (CP-CML) are effectively managed with BCR-ABL1 tyrosine kinase inhibitors (TKIs) and their survival approaches that of age-matched controls [1]. However, only a minority of patients achieve treatment-free remission, while most require long-term TKI therapy to avoid recurrence of active CML, at considerable cost and risk of toxicity [2]. Current thinking holds that quiescent, fully leukemogenic CML stem cells (LSCs) are BCR-ABL1-independent, providing a reservoir of residual leukemia in TKI responders [3]. Multiple mechanisms have been implicated in LSC survival in this setting, but thus far, this has not led to clinical solutions [4]. BCR-ABL1 independence is not limited to residual CML, as many patients with clinical TKI resistance do not exhibit explanatory BCR-ABL1 kinase mutations, suggesting that alternative mechanisms support leukemia cell survival. There is overlap in the pathways enabling CML cell survival in these two scenarios. For instance, Wnt/β-catenin and PP2A have been implicated as mediators both of LSC survival and BCR-ABL1-independent TKI resistance [4].

Many malignant cells upregulate CRM1 (chromosome region maintenance 1/exportin 1)-dependent nuclear-cytoplasmic transport (NCT) to inactivate tumor suppressor proteins, and CRM1 inhibitors such as selinexor (KPT-330) are in clinical development for several cancer types, including myeloid malignancies [5, 6]. We have previously shown that CD34+ cells from patients with BCR-ABL1-independent resistance depend on RAN, a small GTPase that provides the concentration gradient driving CRM1-dependent NCT. These cells are sensitive to selinexor and even more to selinexor/imatinib combinations [7]. Based on this finding, we hypothesized that NCT may have a similar, critical function in LSCs, and that selinexor may synergize with TKIs to eliminate primitive CML cells.

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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.

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Acknowledgements

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.

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Author notes

  1. These authors contributed equally: Hein Than, Anthony D. Pomicter

  2. These authors jointly supervised this work: Clinton C. Mason, Thomas O’Hare, Michael W. Deininger

Authors and Affiliations

  1. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Hein Than, Anthony D. Pomicter, Dongqing Yan, Larry P. Beaver, Anna M. Eiring, William L. Heaton, Anna Senina, Phillip M. Clair, Thomas O’ Hare & Michael W. Deininger

  2. Department of Hematology, Singapore General Hospital, Singapore, Singapore

    Hein Than

  3. Karyopharm Therapeutics, Inc, Newton, MA, USA

    Sharon Shacham

  4. Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, UT, USA

    Clinton C. Mason

  5. Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA

    Thomas O’ Hare & Michael W. Deininger

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Contributions

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.

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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.

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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). https://doi.org/10.1038/s41375-020-0708-1

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