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