Table 1.
Mechanisms contributing to glucocorticoid resistance in lymphoid malignancies
| Type of mechanism | Specific examples | Ref. |
|---|---|---|
| Altered GR expression and function | Differential expression of alternatively spliced and translated GR isoforms | [68-71,73-78,97,98] |
| Transcriptional autoregulation of NR3C1 | [80,81,85] | |
| NR3C1 gene deletions and mutations | [86-89] | |
| Regulation of GR by microRNAs | [90-92] | |
| Degradation of GR by NLRP3-CASP1 inflammasome | [94] | |
| Inhibition of apoptosis | BCL2 translocation | [102] |
| Differential BIM expression | [105-121] | |
| Altered MCL1 expression | [122-127] | |
| Loss-of-function mutations in PRC2 complex proteins (EZH2, EED, SUZ12) | [128] | |
| Survival signals by stromal cells | [130,131] | |
| Activation of signaling pathways | MAPK pathway | [140] |
| CDK-dependent GR phosphorylation | [146,147] | |
| PI3K/AKT pathway | [148-153] | |
| LCK signaling | [156] | |
| JAK/STAT pathway | [160] | |
| Metabolism/mTOR signaling | [161-163] | |
| NOTCH1 pathway | [165-167] | |
| Modulation of GR-mediated transcription regulation | Reduced expression of SWI/SNF chromatin remodeling complex proteins | [122,171] |
| IKZF1, BTG1, TBL1XR1 and CREBBP gene deletions/mutations affect GR target gene regulation | [179-187] | |
| Chromatin accessibility BIM locus | [190] |
GR: glucocorticoid receptor; MCL: mantle cell lymphoma; PI3K: phosphatidylinositol 3-kinase; CDK: cyclin-dependent kinase