Abstract
Despite the introduction of many novel therapies into the clinic to target hematological malignancies, glucocorticoids (GCs) still remain one of the cornerstone drugs in first-line treatment of lymphoid tumors. However, a significant portion of the patients display acquired GC therapy resistance. This review will describe the different molecular mechanisms that contribute to GC resistance in lymphoid tumors. These include suppression of glucocorticoid receptor (GR) expression, activation of cell signaling pathways that modulate GR function, differential recruitment of transcriptional co-regulators, and changes in chromatin accessibility. Many of these mechanisms are interconnected to genetic alterations associated with relapsed disease in lymphoid malignancies.
Highlights
Glucocorticoids (GCs) are primary stress hormones that maintain homeostasis and control a broad range of physiological processes, including immune system function, skeletal growth, reproduction, metabolism, energy production and central nervous system function[1]
Attenuation of glucocorticoid receptor (GR)-mediated transcription regulation both at the level of GC-induced gene activation and repression has been observed in IKZF1-deleted BCP-acute lymphoblastic leukemia (ALL), which is associated with inferior treatment outcome, relapsed disease and reduced GC-sensitivity . [179,180,181] Focal BTG1 deletions further enhance this phenotype[182], which correlates with the ability of BTG1 to regulate GR-dependent transcription[183]
This study revealed that the selective induction of proapoptotic gene BIM(BCL2L11) in GC-sensitive ALL samples correlates with a defined open and active chromatin structure at an intronic GR-binding region within the BIM locus together with recruitment of the chromatin architectural protein CTCF to this site
Summary
Glucocorticoids (GCs) are primary stress hormones that maintain homeostasis and control a broad range of physiological processes, including immune system function, skeletal growth, reproduction, metabolism, energy production and central nervous system function[1]. Extensive research on the mechanism of action of GCs and GR protein function in mediating sensitivity and specificity of the different biological responses, has made an important contribution in unraveling the complexity of GC signaling and its regulation.
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