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 ChengWenjian 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

127 Citations (Scopus)

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)	607-14
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	6
DOIs	https://doi.org/10.1038/ng.3283
Publication status	Published - Jun 2015
Externally published	Yes

Keywords

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
Prednisolone/pharmacology
Proteolysis
Receptors, Glucocorticoid/metabolism
Transcription, Genetic
Tumor Cells, Cultured
Up-Regulation

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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), 607-14. 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. ",

keywords = "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, Prednisolone/pharmacology, Proteolysis, Receptors, Glucocorticoid/metabolism, Transcription, Genetic, Tumor Cells, Cultured, Up-Regulation",

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 Ching-Hon Pui and Myers, {Richard M} and Guy, {R Kiplin} and Thirumala-Devi Kanneganti and Relling, {Mary V} and Evans, {William E}",

year = "2015",

month = jun,

doi = "10.1038/ng.3283",

language = "English",

volume = "47",

pages = "607--14",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

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, C-H, Myers, RM, Guy, RK, Kanneganti, T-D, 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. 607-14. https://doi.org/10.1038/ng.3283

TY - JOUR

T1 - NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells

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

AU - Holmfeldt, Linda

AU - Mullighan, Charles G

AU - den Boer, Monique L

AU - Pieters, Rob

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 - 2015/6

Y1 - 2015/6

N2 - 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.

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.

KW - Adolescent

KW - Antineoplastic Agents, Hormonal/pharmacology

KW - Base Sequence

KW - Carrier Proteins/metabolism

KW - Caspase 1/metabolism

KW - Child

KW - Child, Preschool

KW - DNA Methylation

KW - Drug Resistance, Neoplasm

KW - Drug Screening Assays, Antitumor

KW - Gene Expression Regulation, Leukemic

KW - HEK293 Cells

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Inflammasomes/metabolism

KW - NLR Family, Pyrin Domain-Containing 3 Protein

KW - Neoplasm Recurrence, Local/enzymology

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy

KW - Prednisolone/pharmacology

KW - Proteolysis

KW - Receptors, Glucocorticoid/metabolism

KW - Transcription, Genetic

KW - Tumor Cells, Cultured

KW - Up-Regulation

UR - http://www.scopus.com/inward/record.url?scp=84930088053&partnerID=8YFLogxK

U2 - 10.1038/ng.3283

DO - 10.1038/ng.3283

M3 - Article

C2 - 25938942

SN - 1061-4036

VL - 47

SP - 607

EP - 614

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

Abstract

Keywords

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