Biology Platform, Sunnybrook Research Institute, M4N 3M5, Toronto, ON, Canada.
College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
Leukemia. 2019 Jul;33(7):1650-1662. doi: 10.1038/s41375-019-0381-4. Epub 2019 Jan 29.
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.
研究了糖皮质激素（GC）受体（GR）磷酸化和特征基因在慢性淋巴细胞白血病（CLL）细胞中的作用，以帮助将 GCs 纳入现代治疗方案。与正常 B 和 T 细胞不同，GC 调节基因的转录没有节律性，合成 GC 地塞米松（DEX）不能抑制 CLL 细胞中的 Toll 样受体（TLR）反应。这种内在的 GC 耐药性与异常的 GR 磷酸化有关，包括激活 Ser211 和抑制 Ser226 位点。依鲁替尼可增加循环 CLL 细胞中 GR 特征基因 GILZ 的转录，同时增加 GR(pS211)/GR(pS226) 比值，并增加对 DEX 的裂解敏感性，但在体外用竞争性拮抗剂米非司酮不能逆转。然而，依鲁替尼不能改善用 IL2 和 TLR7/8 激动剂激活的循环 CLL 细胞中的 GR 反应，以模拟假滤泡微环境中的条件。添加 Janus 激酶抑制剂鲁索替尼以阻断依鲁替尼不敏感的信号，可增加体外假滤泡条件下和临床试验（NCT02912754）中的 GILZ 转录，并增加患者样本中 GR(S211)/GR(S226) 比值和 DEX 介导的杀伤。这些观察结果表明，内源性 GCs 的固有耐药性是 CLL 细胞的特征，依鲁替尼可能通过 GR 的非经典激活来增加 GCs 的治疗活性。
