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Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells

Leukemia volume 28, pages 1158–1163 (2014)Cite this article

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Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of clonal mature B cells in the blood, bone marrow and secondary lymphoid organs. Although peripheral CLL is quiescent, up to 1% of clonal cells are generated daily within proliferative centers.1 CLL cells isolated from these structures display activation of survival and proliferation pathways (for example, phosphatidylinositol 3-Kinase (PI3K), Bruton’s tyrosine kinase (BTK) and nuclear factor (NF-κB))1 because of interactions with accessory cells. In CLL, B-cell receptor (BCR) signaling represents one of the central pathways known to enhance survival and proliferation. The importance of BCR signaling in CLL pathogenesis is underscored by the prognostic significance of somatic mutations in the immunoglobulin heavy-chain variable regions (IGHV) of the BCR. In general, CLL patients with unmutated IGHV have shorter progression-free survival and lower response rates.2 CLL cells isolated from patients with unmutated IGHV rely heavily on survival signals and respond preferentially to BCR and Toll-like receptor 9 (TLR9) stimulation,3 suggesting that therapies that block these signals may be particularly effective in this aggressive subset of CLL.

The recently unveiled mechanisms that control CLL cell survival and expansion have prompted the rapid development of therapeutics that disrupt CLL–microenvironment interactions and block BCR-driven activation (that is, fostamatinib, idelalisib and ibrutinib)4, 5, 6, 7 and have demonstrated profound clinical activity.4, 5 Unfortunately, some patients do not respond or develop resistance, emphasizing the importance of alternative therapeutic strategies.5

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Acknowledgements

We are grateful to the patients who provided blood for the above-mentioned studies, research support from The Leukemia and Lymphoma Society in the form of a translational grant and Specialized Center of Research, and the National Cancer Institute (P50 CA140158 and 1K12 CA133250). We are grateful to Alan Flechtner and the Comparative Pathology and Mouse Phenotyping Shared Resource at the Ohio State University for their technical support with the immunohistochemical studies. In addition, we thank Karyopharm Therapeutics for providing funds for a subset of the SCID mice used in this investigation.

Author Contributions

YZ, RL and JCB designed the experiments, analyzed the data, wrote the paper and reviewed and approved the final version. DE, JAD, KAB, BKH, KEW, VMG, SJ, XM, JAJ, JMF, KJM, LAA, DM, SS and MK planned and contributed to components of the experimental work presented (chemical, biological, clinical or animal studies), reviewed and modified versions of the paper and approved the final version.

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Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    Y Zhong, D El-Gamal, J A Dubovsky, K A Beckwith, K E Williams, V M Goettl, S Jha, J A Jones, J M Flynn, K J Maddocks, L A Andritsos, J C Byrd & R Lapalombella

  2. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA

    B K Harrington

  3. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    X Mo

  4. Karyopharm Therapeutics Inc., Natick, MA, USA

    D McCauley, S Shacham & M Kauffman

  5. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    J C Byrd

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  1. Y Zhong
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  2. D El-Gamal
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  18. R Lapalombella
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Corresponding author

Correspondence to R Lapalombella.

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Competing interests

DM, SS and MK are employees of Karyopharm and have financial interests in this company.

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Supplementary Information accompanies this paper on the Leukemia website

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Zhong, Y., El-Gamal, D., Dubovsky, J. et al. Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells. Leukemia 28, 1158–1163 (2014). https://doi.org/10.1038/leu.2014.9

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