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

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

Journal article

Peer reviewed

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, …

Nature genetics, Vol.47(6), pp.607-614

06/2015

DOI: 10.1038/ng.3283

PMCID: PMC4449308

PMID: 25938942

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http://hdl.handle.net/1765/88148View

Open Access

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.

Up-Regulation

Inflammasomes - metabolism

NLR Family, Pyrin Domain-Containing 3 Protein

Humans

Child, Preschool

Caspase 1 - metabolism

Drug Resistance, Neoplasm

Infant

Receptors, Glucocorticoid - metabolism

Neoplasm Recurrence, Local - enzymology

Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy

DNA Methylation

Proteolysis

Base Sequence

HEK293 Cells

Transcription, Genetic

Tumor Cells, Cultured

Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology

Child

Infant, Newborn

Antineoplastic Agents, Hormonal - pharmacology

Gene Expression Regulation, Leukemic

Prednisolone - pharmacology

Carrier Proteins - metabolism

Adolescent

Precursor Cell Lymphoblastic Leukemia-Lymphoma - enzymology

Drug Screening Assays, Antitumor

Details

Title: Subtitle: NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells
Creators: Steven W Paugh - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Erik J Bonten - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Daniel Savic - HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
Laura B Ramsey - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
William E Thierfelder - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Prajwal Gurung - Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
R K Subbarao Malireddi - Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Marcelo Actis - Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Anand Mayasundari - Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Jaeki Min - Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
David R Coss - High-Performance Computing Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Lucas T Laudermilk - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
John C Panetta - Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
J Robert McCorkle - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Yiping Fan - Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Kristine R Crews - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Gabriele Stocco - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Mark R Wilkinson - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Antonio M Ferreira - High-Performance Computing Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Cheng Cheng - Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Wenjian Yang - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Seth E Karol - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Christian A Fernandez - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Barthelemy Diouf - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Colton Smith - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
J Kevin Hicks - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Alessandra Zanut - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Audrey Giordanengo - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Daniel Crona - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Joy J Bianchi - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Linda Holmfeldt - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Charles G Mullighan - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Monique L den Boer - Division of Pediatric Oncology-Hematology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands
Rob Pieters - 1] Division of Pediatric Oncology-Hematology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Sima Jeha - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Thomas L Dunwell - Centre for Rare Diseases and Personalized Medicine, University of Birmingham, Birmingham, UK
Farida Latif - Centre for Rare Diseases and Personalized Medicine, University of Birmingham, Birmingham, UK
Deepa Bhojwani - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
William L Carroll - New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA
Ching-Hon Pui - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Richard M Myers - HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
R Kiplin Guy - Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Thirumala-Devi Kanneganti - Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Mary V Relling - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
William E Evans - 1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Resource Type: Journal article
Publication Details: Nature genetics, Vol.47(6), pp.607-614
DOI: 10.1038/ng.3283
PMID: 25938942
PMCID: PMC4449308
NLM abbreviation: Nat Genet
ISSN: 1061-4036
eISSN: 1546-1718
Grant note: R25 CA023944 / NCI NIH HHS R37CA36401 / NCI NIH HHS U01GM92666 / NIGMS NIH HHS F32CA141762 / NCI NIH HHS F32 CA141762 / NCI NIH HHS 3R37CA036401-26S1 / NCI NIH HHS R01 CA163507 / NCI NIH HHS U01 GM092666 / NIGMS NIH HHS R37 CA036401 / NCI NIH HHS P30 CA021765 / NCI NIH HHS CA21765 / NCI NIH HHS
Language: English
Date published: 06/2015
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094532902771

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