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

Abstract

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.

• Authors: Steven W Paugh, Erik J Bonten, Daniel Savic, Laura B Ramsey, William E Thierfelder, Prajwal Gurung, R K Subbarao Malireddi, Marcelo Actis, Anand Mayasundari, Jaeki Min, David R Coss, Lucas T Laudermilk, John C Panetta, J Robert McCorkle, Yiping Fan, Kristine R Crews, Gabriele Stocco, Mark R Wilkinson, Antonio M Ferreira, Cheng Cheng, Wenjian Yang, Seth E Karol, Christian A Fernandez, Barthelemy Diouf, Colton Smith, J Kevin Hicks, Alessandra Zanut, Audrey Giordanengo, Daniel Crona, Joy J Bianchi, Linda Holmfeldt, Charles G Mullighan, Monique L den Boer, Rob Pieters, Sima Jeha, Thomas L Dunwell, Farida Latif, Deepa Bhojwani, William L Carroll, Ching-Hon Pui, Richard M Myers, R Kiplin Guy, Thirumala-Devi Kanneganti, Mary V Relling, William E Evans
• Journal: Nature genetics (Nat Genet) Vol. 47 Issue 6 Pg. 607-14 (Jun 2015) ISSN: 1546-1718 [Electronic] United States
• PMID: 25938942 (Publication Type: Journal Article, Research Support, American Recovery and Reinvestment Act, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Carrier Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Receptors, Glucocorticoid
• Prednisolone
• Caspase 1

Topics

• Adolescent
• Antineoplastic Agents, Hormonal (pharmacology)
• Base Sequence
• Carrier Proteins (metabolism)
• Caspase 1 (metabolism)
• Child
• Child, Preschool
• DNA Methylation
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Gene Expression Regulation, Leukemic
• HEK293 Cells
• Humans
• Infant
• Infant, Newborn
• Inflammasomes (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Neoplasm Recurrence, Local (enzymology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, enzymology, pathology)
• Prednisolone (pharmacology)
• Proteolysis
• Receptors, Glucocorticoid (metabolism)
• Transcription, Genetic
• Tumor Cells, Cultured
• Up-Regulation