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NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells
Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and leukemia cell resistant to glucocorticoids confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the sensitivity to prednisolone of primary leukemia cells from 444...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
2015
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449308/ https://www.ncbi.nlm.nih.gov/pubmed/25938942 http://dx.doi.org/10.1038/ng.3283 |
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| author | Paugh, Steven W. Bonten, Erik J. Savic, Daniel Ramsey, Laura B. Thierfelder, William E. Gurung, Prajwal Malireddi, R. K. Subbarao Actis, Marcelo Mayasundari, Anand Min, Jaeki Coss, David R. Laudermilk, Lucas T. Panetta, John C. McCorkle, J. Robert Fan, Yiping Crews, Kristine R. Stocco, Gabriele Wilkinson, Mark R. Ferreira, Antonio M. Cheng, Cheng Yang, Wenjian Karol, Seth E. Fernandez, Christian A. Diouf, Barthelemy Smith, Colton Hicks, J. Kevin Zanut, Alessandra Giordanengo, Audrey Crona, Daniel Bianchi, Joy J. Holmfeldt, Linda Mullighan, Charles G. den Boer, Monique L. Pieters, Rob Jeha, Sima Dunwell, Thomas L. Latif, Farida Bhojwani, Deepa Carroll, William L. Pui, Ching-Hon Myers, Richard M. Guy, R. Kiplin Kanneganti, Thirumala-Devi Relling, Mary V. Evans, William E. |
| author_facet | Paugh, Steven W. Bonten, Erik J. Savic, Daniel Ramsey, Laura B. Thierfelder, William E. Gurung, Prajwal Malireddi, R. K. Subbarao Actis, Marcelo Mayasundari, Anand Min, Jaeki Coss, David R. Laudermilk, Lucas T. Panetta, John C. McCorkle, J. Robert Fan, Yiping Crews, Kristine R. Stocco, Gabriele Wilkinson, Mark R. Ferreira, Antonio M. Cheng, Cheng Yang, Wenjian Karol, Seth E. Fernandez, Christian A. Diouf, Barthelemy Smith, Colton Hicks, J. Kevin Zanut, Alessandra Giordanengo, Audrey Crona, Daniel Bianchi, Joy J. Holmfeldt, Linda Mullighan, Charles G. den Boer, Monique L. Pieters, Rob Jeha, Sima Dunwell, Thomas L. Latif, Farida Bhojwani, Deepa Carroll, William L. Pui, Ching-Hon Myers, Richard M. Guy, R. Kiplin Kanneganti, Thirumala-Devi Relling, Mary V. Evans, William E. |
| author_sort | Paugh, Steven W. |
| collection | PubMed |
| description | Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and leukemia cell resistant to glucocorticoids confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the sensitivity to prednisolone of primary leukemia cells from 444 newly diagnosed ALL patients, revealing 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. |
| format | Online Article Text |
| id | pubmed-4449308 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2015 |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-44493082015-12-01 NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells Paugh, Steven W. Bonten, Erik J. Savic, Daniel Ramsey, Laura B. Thierfelder, William E. Gurung, Prajwal Malireddi, R. K. Subbarao Actis, Marcelo Mayasundari, Anand Min, Jaeki Coss, David R. Laudermilk, Lucas T. Panetta, John C. McCorkle, J. Robert Fan, Yiping Crews, Kristine R. Stocco, Gabriele Wilkinson, Mark R. Ferreira, Antonio M. Cheng, Cheng Yang, Wenjian Karol, Seth E. Fernandez, Christian A. Diouf, Barthelemy Smith, Colton Hicks, J. Kevin Zanut, Alessandra Giordanengo, Audrey Crona, Daniel Bianchi, Joy J. Holmfeldt, Linda Mullighan, Charles G. den Boer, Monique L. Pieters, Rob Jeha, Sima Dunwell, Thomas L. Latif, Farida Bhojwani, Deepa Carroll, William L. Pui, Ching-Hon Myers, Richard M. Guy, R. Kiplin Kanneganti, Thirumala-Devi Relling, Mary V. Evans, William E. Nat Genet Article Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and leukemia cell resistant to glucocorticoids confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the sensitivity to prednisolone of primary leukemia cells from 444 newly diagnosed ALL patients, revealing 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. 2015-05-04 2015-06 /pmc/articles/PMC4449308/ /pubmed/25938942 http://dx.doi.org/10.1038/ng.3283 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
| spellingShingle | Article Paugh, Steven W. Bonten, Erik J. Savic, Daniel Ramsey, Laura B. Thierfelder, William E. Gurung, Prajwal Malireddi, R. K. Subbarao Actis, Marcelo Mayasundari, Anand Min, Jaeki Coss, David R. Laudermilk, Lucas T. Panetta, John C. McCorkle, J. Robert Fan, Yiping Crews, Kristine R. Stocco, Gabriele Wilkinson, Mark R. Ferreira, Antonio M. Cheng, Cheng Yang, Wenjian Karol, Seth E. Fernandez, Christian A. Diouf, Barthelemy Smith, Colton Hicks, J. Kevin Zanut, Alessandra Giordanengo, Audrey Crona, Daniel Bianchi, Joy J. Holmfeldt, Linda Mullighan, Charles G. den Boer, Monique L. Pieters, Rob Jeha, Sima Dunwell, Thomas L. Latif, Farida Bhojwani, Deepa Carroll, William L. Pui, Ching-Hon Myers, Richard M. Guy, R. Kiplin Kanneganti, Thirumala-Devi Relling, Mary V. Evans, William E. NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells |
| title | NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells |
| title_full | NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells |
| title_fullStr | NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells |
| title_full_unstemmed | NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells |
| title_short | NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells |
| title_sort | nalp3 inflammasome up-regulation and casp1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449308/ https://www.ncbi.nlm.nih.gov/pubmed/25938942 http://dx.doi.org/10.1038/ng.3283 |
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