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

被引：134

作者：

Paugh, Steven W. ^{[1
,2
]}

Bonten, Erik J. ^{[1
,2
]}

Savic, Daniel ^{[3
]}

Ramsey, Laura B. ^{[1
,2
]}

Thierfelder, William E. ^{[1
,2
]}

Gurung, Prajwal ^{[4
]}

Malireddi, R. K. Subbarao ^{[4
]}

Actis, Marcelo ^{[5
]}

Mayasundari, Anand ^{[5
]}

Min, Jaeki ^{[5
]}

Coss, David R. ^{[6
]}

Laudermilk, Lucas T. ^{[1
,2
]}

Panetta, John C. ^{[2
]}

McCorkle, J. Robert ^{[1
,2
]}

Fan, Yiping ^{[7
]}

Crews, Kristine R. ^{[1
,2
]}

Stocco, Gabriele ^{[1
,2
]}

Wilkinson, Mark R. ^{[1
,2
]}

Ferreira, Antonio M. ^{[6
]}

Cheng, Cheng ^{[8
]}

Yang, Wenjian ^{[1
,2
]}

Karol, Seth E. ^{[1
,2
,9
]}

Fernandez, Christian A. ^{[1
,2
]}

Diouf, Barthelemy ^{[1
,2
]}

Smith, Colton ^{[1
,2
]}

Hicks, J. Kevin ^{[1
,2
]}

Zanut, Alessandra ^{[1
,2
]}

Giordanengo, Audrey ^{[1
,2
]}

Crona, Daniel ^{[1
,2
]}

Bianchi, Joy J. ^{[1
,2
]}

Holmfeldt, Linda ^{[1
,10
]}

Mullighan, Charles G. ^{[1
,10
]}

den Boer, Monique L. ^{[11
]}

Pieters, Rob ^{[11
,12
]}

Jeha, Sima ^{[1
,9
]}

Dunwell, Thomas L. ^{[13
]}

Latif, Farida ^{[13
]}

Bhojwani, Deepa ^{[1
,9
]}

Carroll, William L. ^{[14
]}

Pui, Ching-Hon ^{[1
,9
]}

Myers, Richard M. ^{[3
]}

Guy, R. Kiplin ^{[5
]}

Kanneganti, Thirumala-Devi

Relling, Mary V. ^{[1
,2
]}

Evans, William E. ^{[1
,2
]}

机构：

[1] St Jude Childrens Res Hosp, Hematol Malignancies Program, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

[3] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[4] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

[5] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA

[6] St Jude Childrens Res Hosp, High Performance Comp Facil, Memphis, TN 38105 USA

[7] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA

[8] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA

[9] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA

[10] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[11] Erasmus Univ, Med Ctr, Sophia Childrens Hosp, Div Pediat Oncol Hematol, Rotterdam, Netherlands

[12] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands

[13] Univ Birmingham, Ctr Rare Dis & Personalized Med, Birmingham, W Midlands, England

[14] NYU, Langone Med Ctr, Inst Canc, New York, NY USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 06期

基金：

美国国家卫生研究院;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; INTERLEUKIN-1-BETA CONVERTING-ENZYME; CELLULAR-DRUG RESISTANCE; GENE; ACTIVATION; INHIBITION; CHROMATIN; MECHANISMS; CHILDREN; STRESS;

D O I：

10.1038/ng.3283

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：607 / 614

页数：8

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