39 research outputs found
Effects of Guideline and Formulary Changes on Statin Prescribing in the Veterans Affairs
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139955/1/hesr12788-sup-0001-AppendixSA1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139955/2/hesr12788_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139955/3/hesr12788.pd
NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells
Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 patients newly diagnosed with ALL and found significantly higher expression of CASP1 (encoding caspase 1) and its activator NLRP3 in glucocorticoid-resistant leukemia cells, resulting from significantly lower somatic methylation of the CASP1 and NLRP3 promoters. Overexpression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished the glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1-overexpressing ALL. Our findings establish a new mechanism by which the NLRP3-CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on the glucocorticoid transcriptional response suggests that this mechanism could also modify glucocorticoid effects in other diseases
Transcription profiling of human primary ALL cells (B-lineage) sensitive to prednisolone by the MTT in vitro sensitivity assay
primary ALL cells (B-lineage) sensitive to prednisolone by the MTT in vitro sensitivity assa
Transcription profiling of primary ALL cells (B-lineage) resistant to vincristine by the MTT in vitro sensitivity assay
primary ALL cells (B- and T-lineage) resistant to vincristine by the MTT in vitro sensitivity assa
Transcription profiling of ALL cells resistant prednisalone
primary ALL cells (B-lineage) resistant to prednisolone by the MTT in vitro sensitivity assa
Transcription profiling of ALL cells resistant prednisalone
primary ALL cells (B-lineage) resistant to prednisolone by the MTT in vitro sensitivity assa
Transcription profiling of human primary ALL cells (B- and T-lineage) resistant to prednisolone by the MTT in vitro sensitivity assay
primary ALL cells (B- and T-lineage) resistant to prednisolone by the MTT in vitro sensitivity assa
Transcription profiling of human primary ALL cells (B- and T-lineage) resistant to prednisolone by the MTT in vitro sensitivity assay
primary ALL cells (B- and T-lineage) resistant to prednisolone by the MTT in vitro sensitivity assa
Transcription profiling of human L-asparaginase drug resistant acute lymphoblastic leukemia cells
primary ALL cells (B- and T-lineage) resistant to L-asparaginase by the MTT in vitro sensitivity assa