NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.
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.
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Steven W
0000000156979228
SW
Paugh
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Erik J
EJ
Bonten
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
Daniel
D
Savic
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Laura B
LB
Ramsey
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
William E
WE
Thierfelder
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Prajwal
P
Gurung
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
R K Subbarao
RK
Malireddi
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Marcelo
M
Actis
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Anand
A
Mayasundari
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jaeki
J
Min
High-Performance Computing Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
David R
DR
Coss
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Lucas T
LT
Laudermilk
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
John C
JC
Panetta
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
J Robert
JR
McCorkle
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Yiping
Y
Fan
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Kristine R
KR
Crews
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Gabriele
0000000309645879
G
Stocco
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Mark R
MR
Wilkinson
High-Performance Computing Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Antonio M
AM
Ferreira
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Cheng
C
Cheng
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Wenjian
W
Yang
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [3] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Seth E
SE
Karol
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Christian A
CA
Fernandez
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Barthelemy
0000000239470611
B
Diouf
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Colton
C
Smith
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
J Kevin
JK
Hicks
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Alessandra
A
Zanut
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Audrey
A
Giordanengo
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Daniel
D
Crona
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Joy J
JJ
Bianchi
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Linda
0000000341403423
L
Holmfeldt
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Charles G
0000000218711850
CG
Mullighan
Division of Pediatric Oncology-Hematology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands.
Monique L
ML
den Boer
1] Division of Pediatric Oncology-Hematology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands. [2] Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Rob
R
Pieters
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Sima
S
Jeha
Centre for Rare Diseases and Personalized Medicine, University of Birmingham, Birmingham, UK.
Thomas L
TL
Dunwell
Centre for Rare Diseases and Personalized Medicine, University of Birmingham, Birmingham, UK.
Farida
F
Latif
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Deepa
D
Bhojwani
New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA.
William L
WL
Carroll
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Ching-Hon
CH
Pui
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
Richard M
RM
Myers
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
R Kiplin
RK
Guy
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Thirumala-Devi
TD
Kanneganti
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Mary V
MV
Relling
1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
William E
WE
Evans
D000293:Adolescent; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D058847:Inflammasomes / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009364:Neoplasm Recurrence, Local / Q000201:enzymology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D059748:Proteolysis; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018931:Antineoplastic Agents, Hormonal; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011965:Receptors, Glucocorticoid; D011239:Prednisolone; D020170:Caspase 1