Genomics

Dataset Information

51

NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells [HG-U133_Plus_2]


ABSTRACT: Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and glucocorticoid resistance in leukemia cells confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 newly diagnosed ALL patients and found significantly higher expression of caspase 1 (CASP1) and its activator NLRP3 in glucocorticoid resistant leukemia cells, due to significantly lower somatic methylation of CASP1 and NLRP3 promoters. Over-expression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished 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 glucocorticoid transcriptional response suggests this mechanism could also modify glucocorticoid effects in other diseases. Overall design: Gene expression profiling

INSTRUMENT(S): [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array

SUBMITTER: Steven William Paugh  

PROVIDER: GSE66705 | GEO | 2015-03-24

SECONDARY ACCESSION(S): PRJNA277765

REPOSITORIES: GEO

Dataset's files

Source:
Action DRS
GSE66705_RAW.tar Raw
filelist.txt Txt
Items per page:
1 - 2 of 2
altmetric image

Publications

NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.

Paugh Steven W SW   Bonten Erik J EJ   Savic Daniel D   Ramsey Laura B LB   Thierfelder William E WE   Gurung Prajwal P   Malireddi R K Subbarao RK   Actis Marcelo M   Mayasundari Anand A   Min Jaeki J   Coss David R DR   Laudermilk Lucas T LT   Panetta John C JC   McCorkle J Robert JR   Fan Yiping Y   Crews Kristine R KR   Stocco Gabriele G   Wilkinson Mark R MR   Ferreira Antonio M AM   Cheng Cheng C   Yang Wenjian W   Karol Seth E SE   Fernandez Christian A CA   Diouf Barthelemy B   Smith Colton C   Hicks J Kevin JK   Zanut Alessandra A   Giordanengo Audrey A   Crona Daniel D   Bianchi Joy J JJ   Holmfeldt Linda L   Mullighan Charles G CG   den Boer Monique L ML   Pieters Rob R   Jeha Sima S   Dunwell Thomas L TL   Latif Farida F   Bhojwani Deepa D   Carroll William L WL   Pui Ching-Hon CH   Myers Richard M RM   Guy R Kiplin RK   Kanneganti Thirumala-Devi TD   Relling Mary V MV   Evans William E WE  

Nature genetics 20150504 6


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 significan  ...[more]

Similar Datasets

2015-01-01 | S-EPMC4449308 | BioStudies
2015-03-24 | GSE67046 | GEO
2015-03-24 | GSE67044 | GEO
2015-03-24 | GSE67045 | GEO
2015-03-24 | GSE67042 | GEO
2015-03-24 | GSE66702 | GEO
2015-03-24 | GSE67043 | GEO
2015-03-24 | GSE66400 | GEO
2010-01-01 | S-EPMC2846044 | BioStudies
2008-01-01 | S-EPMC2639326 | BioStudies