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

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

doi:10.1038/ng.3283

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

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

Research output: Contribution to journal › Article › peer-review

155 Scopus citations

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.

Original language	English
Pages (from-to)	607-614
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	6
DOIs	https://doi.org/10.1038/ng.3283
State	Published - May 27 2015

Bibliographical note

Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.

Funding

We gratefully acknowledge the patients and their parents who participated in this research. We are appreciative of the expert technical assistance of M. Roberts, Y. Chu, Y. Wang, M.A. Payton, J. Stukenborg, S. Salehy, M. Needham, M. Chung, N. Lenchik, M. Loyd and E. Walker. We thank J. Groff and E. Stevens for figure preparation assistance and C. Simmons for assistance with manuscript preparation. We thank D. Green for his scientific advice and discussion of the manuscript. We thank C. Stewart, G. Neale, J. Morris and K. Rakestraw for their technical advice and expertise. This work was supported in part by US National Institutes of Health (NIH) National Cancer Institute grant R37CA36401 (W.E.E., M.V.R. and C.-H.P.), US NIH National Institute of General Medical Sciences Pharmacogenomics Research Network grant U01GM92666 (M.V.R. and W.E.E.), US NIH grant F32CA141762 (S.W.P.) and an American Recovery and Reinvestment Act supplement, 3R37CA036401-26S1 (W.E.E.). This work was also supported by Cancer Center Support Grant CA21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funders	Funder number
Markey Cancer Center's Cancer Center Support	CA21765
NIH National Institute of General Medical Sciences Pharmacogenomics Research Network	3R37CA036401-26S1, U01GM92666
US National Institutes for Health
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	R37CA36401, F32CA141762, R01CA163507
American Lebanese Syrian Associated Charities

ASJC Scopus subject areas

Genetics

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10.1038/ng.3283

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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., ... Evans, W. E. (2015). NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nature Genetics, 47(6), 607-614. https://doi.org/10.1038/ng.3283

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title = "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.",

author = "Paugh, \{Steven W.\} and Bonten, \{Erik J.\} and Daniel Savic and Ramsey, \{Laura B.\} and Thierfelder, \{William E.\} and Prajwal Gurung and Malireddi, \{R. K.Subbarao\} and Marcelo Actis and Anand Mayasundari and Jaeki Min and Coss, \{David R.\} and Laudermilk, \{Lucas T.\} and Panetta, \{John C.\} and McCorkle, \{J. Robert\} and Yiping Fan and Crews, \{Kristine R.\} and Gabriele Stocco and Wilkinson, \{Mark R.\} and Ferreira, \{Antonio M.\} and Cheng Cheng and Wenjian Yang and Karol, \{Seth E.\} and Fernandez, \{Christian A.\} and Barthelemy Diouf and Colton Smith and Hicks, \{J. Kevin\} and Alessandra Zanut and Audrey Giordanengo and Daniel Crona and Bianchi, \{Joy J.\} and Linda Holmfeldt and Mullighan, \{Charles G.\} and \{Den Boer\}, \{Monique L.\} and Rob Pieters and Sima Jeha and Dunwell, \{Thomas L.\} and Farida Latif and Deepa Bhojwani and Carroll, \{William L.\} and Pui, \{Ching Hon\} and Myers, \{Richard M.\} and Guy, \{R. Kiplin\} and Kanneganti, \{Thirumala Devi\} and Relling, \{Mary V.\} and Evans, \{William E.\}",

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Paugh, SW, Bonten, EJ, Savic, D, Ramsey, LB, Thierfelder, WE, Gurung, P, Malireddi, RKS, Actis, M, Mayasundari, A, Min, J, Coss, DR, Laudermilk, LT, Panetta, JC, McCorkle, JR, Fan, Y, Crews, KR, Stocco, G, Wilkinson, MR, Ferreira, AM, Cheng, C, Yang, W, Karol, SE, Fernandez, CA, Diouf, B, Smith, C, Hicks, JK, Zanut, A, Giordanengo, A, Crona, D, Bianchi, JJ, Holmfeldt, L, Mullighan, CG, Den Boer, ML, Pieters, R, Jeha, S, Dunwell, TL, Latif, F, Bhojwani, D, Carroll, WL, Pui, CH, Myers, RM, Guy, RK, Kanneganti, TD, Relling, MV & Evans, WE 2015, 'NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells', Nature Genetics, vol. 47, no. 6, pp. 607-614. https://doi.org/10.1038/ng.3283

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AU - Paugh, Steven W.

AU - Bonten, Erik J.

AU - Savic, Daniel

AU - Ramsey, Laura B.

AU - Thierfelder, William E.

AU - Gurung, Prajwal

AU - Malireddi, R. K.Subbarao

AU - Actis, Marcelo

AU - Mayasundari, Anand

AU - Min, Jaeki

AU - Coss, David R.

AU - Laudermilk, Lucas T.

AU - Panetta, John C.

AU - McCorkle, J. Robert

AU - Fan, Yiping

AU - Crews, Kristine R.

AU - Stocco, Gabriele

AU - Wilkinson, Mark R.

AU - Ferreira, Antonio M.

AU - Cheng, Cheng

AU - Yang, Wenjian

AU - Karol, Seth E.

AU - Fernandez, Christian A.

AU - Diouf, Barthelemy

AU - Smith, Colton

AU - Hicks, J. Kevin

AU - Zanut, Alessandra

AU - Giordanengo, Audrey

AU - Crona, Daniel

AU - Bianchi, Joy J.

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AU - Jeha, Sima

AU - Dunwell, Thomas L.

AU - Latif, Farida

AU - Bhojwani, Deepa

AU - Carroll, William L.

AU - Pui, Ching Hon

AU - Myers, Richard M.

AU - Guy, R. Kiplin

AU - Kanneganti, Thirumala Devi

AU - Relling, Mary V.

AU - Evans, William E.

PY - 2015/5/27

Y1 - 2015/5/27

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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