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Chronic lymphocytic leukemia

Ibrutinib reprograms the glucocorticoid receptor in chronic lymphocytic leukemia cells

Leukemia volume 33, pages 1650–1662 (2019)Cite this article

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Abstract

Glucocorticoid (GC) receptor (GR) phosphorylation and signature genes were studied in chronic lymphocytic leukemia (CLL) cells to help place GCs within modern treatment algorithms. In contrast to normal B and T cells, transcription of GC-regulated genes was not rhythmic and the synthetic GC dexamethasone (DEX) could not inhibit toll-like receptor (TLR)-responses in CLL cells. This intrinsic GC-resistance was associated with aberrant GR-phosphorylation on activating Ser211 and inhibitory Ser226 sites. Ibrutinib increased transcription of the GR-signature gene GILZ in circulating CLL cells along with GR(pS211)/GR(pS226) ratios and lytic sensitivity to DEX that were not reversed by the competitive antagonist mifepristone in vitro. However, ibrutinib could not improve GR-responses in circulating CLL cells activated with IL2 and TLR7/8 agonists to mimic conditions in pseudofollicle microenvironments. Addition of the janus kinase inhibitor ruxolitinib to block ibrutinib-insensitive signals increased GILZ transcription in pseudofollicle conditions in vitro and in a clinical trial (NCT02912754), and also increased GR(S211)/GR(S226) ratios and DEX-mediated killing in patient samples in vitro. These observations suggest that intrinsic resistance to endogenous GCs is characteristic of CLL cells and ibrutinib may help increase the therapeutic activity of GCs by non-canonical activation of GR.

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Data availability

The data that support the findings of this study are available from the corresponding author (DS) upon request.

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Acknowledgements

This work was supported by CIHR grants FRN130479 and FRN153291, the Leukemia and Lymphoma Society of Canada (DS), and the National Institutes of Health, National Cancer Institute R01 CA197870 (JAW).

Author contributions

YS and DES conceived the project, designed the experiments, and wrote the manuscript. YS and GW performed the experiments. LM helped write manuscript. CW and GB performed gene array analysis for circadian expression and helped write the manuscript. EM and JAW helped designed and performed experiments and helped write revised manuscript.

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Authors and Affiliations

  1. Biology Platform, Sunnybrook Research Institute, M4N 3M5, Toronto, ON, Canada

    Yonghong Shi, Guizhi Wang, Lindsay McCaw & David E. Spaner

  2. College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA

    Elizabeth M. Muhowski & Jennifer A. Woyach

  3. Sunnybrook Odette Cancer Center, M4N 3M5, Toronto, ON, Canada

    Catherine Wang, Georg Bjarnason & David E. Spaner

  4. Department of Medicine, University of Toronto, M5G 2C4, Toronto, ON, Canada

    Georg Bjarnason & David E. Spaner

  5. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA

    Jennifer A. Woyach

  6. Department of Immunology, University of Toronto, M5S 1A8, Toronto, ON, Canada

    David E. Spaner

  7. Department of Medical Biophysics, University of Toronto, M5G 2M9, Toronto, ON, Canada

    David E. Spaner

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  1. Yonghong Shi
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Shi, Y., Wang, G., Muhowski, E.M. et al. Ibrutinib reprograms the glucocorticoid receptor in chronic lymphocytic leukemia cells. Leukemia 33, 1650–1662 (2019). https://doi.org/10.1038/s41375-019-0381-4

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