Overexpression of CASP1 and its activator NLRP3 confers glucocorticoid resistance in ALL.
Major finding: Overexpression of CASP1 and its activator NLRP3 confers glucocorticoid resistance in ALL.
Mechanism: CASP1 decreases glucocorticoid-induced transcription by cleaving the glucocorticoid receptor.
Impact: Small-molecule CASP1 inhibitors may restore glucocorticoid sensitivity in ALL and other diseases.
Glucocorticoid steroid hormones promote apoptosis of acute lymphoblastic leukemia (ALL) cells via activation of glucocorticoid receptor–mediated transcriptional changes and are an important part of treatment for patients with ALL. Resistance to glucocorticoids is associated with poor outcome in children with ALL; however, the mechanisms underlying de novo resistance to glucocorticoids remain poorly understood. Paugh and colleagues identified the genes encoding caspase 1 (CASP1) and its activator NLR family, pyrin domain–containing 3 (NLRP3), which are components of the NLRP3 inflammasome, as two of the most significantly upregulated genes in glucocorticoid-resistant leukemia cells from patients newly diagnosed with ALL. This increase in CASP1 and NLRP3 expression correlated with decreased somatic promoter methylation of both genes in glucocorticoid-resistant leukemia cells. In addition, expression of CASP1 and NLRP3 was higher in leukemia cells at the time of disease relapse as compared with samples obtained at diagnosis. Overexpression of CASP1 resulted in enhanced resistance to glucocorticoids via cleavage of the glucocorticoid receptor, which reduced the binding of glucocorticoid receptor to glucocorticoid response elements across the genome and diminished the transcriptional response to glucocorticoid stimulation. Conversely, depletion of CASP1 or inhibition of its catalytic activity in CASP1-overexpressing ALL cells or primary leukemia cells prevented CASP1-mediated cleavage of the glucocorticoid receptor and resulted in increased glucocorticoid sensitivity. Similarly, expression of a mutant glucocorticoid receptor lacking CASP1 cleavage sites reversed CASP1-induced glucocorticoid resistance. Taken together, these findings highlight upregulation of the NLRP3–CASP1 inflammasome as a mechanism of glucocorticoid resistance in ALL and support the development of small-molecule inhibitors of CASP1 as a potential means to overcome this resistance.