NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells
Open accessAbstract
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.
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Peripheral T cell trafficking in response to glucocorticoids is impaired in patients with depression, possibly due to glucocorticoid resistance from genetically mediated or inflammasome-mediated mechanisms targeting the glucocorticoid receptor.
“Relevant to depression, however, peripheral T cell trafficking in response to glucocorticoids has been shown to be impaired in patients with depression, possibly owing to glucocorticoid resistance as a result of genetically mediated (for example, FKBP5) or inflammasome-mediated mechanisms targeting the glucocorticoid receptor46,115.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [46]
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Experimental — accuracy not yet measuredNLRP3 inflammasome upregulation and caspase-mediated cleavage of the glucocorticoid receptor can cause resistance to the effects of glucocorticoids.
“NLRP3 inflammasome upregulation and caspase-mediated cleavage of the glucocorticoid receptor can cause resistance to the effects of glucocorticoids, which are among the most potent anti-inflammatory hormones in the body46,47.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [46]
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- Authors
- Paugh, S. W., Bonten, E. J., Savic, D., Ramsey, L. B., Thierfelder, W. E., Gurung, P., Malireddi, R. K. S., Actis, M., Mayasundari, A., Min, J., Coss, D. R., Laudermilk, L. T., Panetta, J. C., McCorkle, J. R., Fan, Y., Crews, K. R., Stocco, G., Wilkinson, M. R., Ferreira, A. M., Cheng, C., Yang, W., Karol, S. E., Fernandez, C. A., Diouf, B., Smith, C., Hicks, J. K., Zanut, A., Giordanengo, A., Crona, D., Bianchi, J. J., Holmfeldt, L., Mullighan, C. G., den Boer, M. L., Pieters, R., Jeha, S., Dunwell, T. L., Latif, F., Bhojwani, D., Carroll, W. L., Pui, C.-H., Myers, R. M., Guy, R. K., Kanneganti, T.-D., Relling, M. V., & Evans, W. E.
- Affiliations
- St. Jude Children's Research Hospital (US)
- HudsonAlpha Institute for Biotechnology (US)
- Erasmus MC (NL)
- University of Birmingham (GB)
- NYU Langone Health (US)
- Corresponding author
- Evans, William E
- ORCID
- Paugh, Steven W
- Savic, Daniel
- Ramsey, Laura B
- Gurung, Prajwal
- Malireddi, R K Subbarao
- Min, Jaeki
- 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
- Crona, Daniel
- Bianchi, Joy J
- Holmfeldt, Linda
- Mullighan, Charles G
- Pieters, Rob
- Jeha, Sima
- Dunwell, Thomas L
- Bhojwani, Deepa
- Carroll, William L
- Pui, Ching-Hon
- Myers, Richard M
- Guy, R Kiplin
- Kanneganti, Thirumala-Devi
- Relling, Mary V
- Evans, William E
- Venue
- Nature Genetics
- Published
- 2015-05-04
- Volume
- 47
- Issue
- 6
- Pages
- 607-614
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4449308
- OpenAlex
- W1559296648
- Cited by
- 164
- References
- 53
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 15 · 2023: 13 · 2022: 13 · 2021: 16 · 2020: 19 · 2019: 18 · 2018: 18 · 2017: 5 · 2016: 19 · 2015: 5 · 2012: 1
- FWCI
- 16.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- National Institutes of Health (CA21765))
- National Cancer Institute (R37-CA36401, R01CA163507, GM92666, CA21765, F32CA141762, R37CA036401, 21765, R25CA023944, P30CA021765)
- National Institute of General Medical Sciences (U01GM92666, U01GM092666)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- NLRP3 inflammasome, caspase-1, glucocorticoid resistance, acute lymphoblastic leukemia, DNA methylation, promoter methylation, inflammation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Adolescent, Base Sequence, Carrier Proteins, Child, Child, Preschool, Drug Screening Assays, Antitumor, Humans, Infant, Infant, Newborn, Neoplasm Recurrence, Local, Prednisolone, Receptors, Glucocorticoid, Transcription, Genetic, Tumor Cells, Cultured, Up-Regulation, Gene Expression Regulation, Leukemic, Antineoplastic Agents, Hormonal, Drug Resistance, Neoplasm, DNA Methylation, Caspase 1, Precursor Cell Lymphoblastic Leukemia-Lymphoma, HEK293 Cells, Inflammasomes, Proteolysis
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