NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.
NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.
复制标题
DOI：
10.1038/ng.3283
复制
发表时间：
2015-06
期刊：
影响因子：
30.8
通讯作者：
Evans, William E.
中科院分区：
文献类型：
--
作者：
Paugh, Steven W.;Bonten, Erik J.;Savic, Daniel;Ramsey, Laura B.;Thierfelder, William E.;Gurung, Prajwal;Malireddi, R. K. Subbarao;Actis, Marcelo;Mayasundari, Anand;Min, Jaeki;Coss, David R.;Laudermilk, Lucas T.;Panetta, John C.;McCorkle, J. Robert;Fan, Yiping;Crews, Kristine R.;Stocco, Gabriele;Wilkinson, Mark R.;Ferreira, Antonio M.;Cheng, Cheng;Yang, Wenjian;Karol, Seth E.;Fernandez, Christian A.;Diouf, Barthelemy;Smith, Colton;Hicks, J. Kevin;Zanut, Alessandra;Giordanengo, Audrey;Crona, Daniel;Bianchi, Joy J.;Holmfeldt, Linda;Mullighan, Charles G.;den Boer, Monique L.;Pieters, Rob;Jeha, Sima;Dunwell, Thomas L.;Latif, Farida;Bhojwani, Deepa;Carroll, William L.;Pui, Ching-Hon;Myers, Richard M.;Guy, R. Kiplin;Kanneganti, Thirumala-Devi;Relling, Mary V.;Evans, William E.
糖皮质激素广泛应用于急性淋巴细胞白血病（ALL）的治疗，对糖皮质激素耐药的白血病细胞预后差。为了阐明糖皮质激素抵抗的机制，我们测定了444例新诊断ALL患者的原代白血病细胞对泼尼松龙的敏感性，揭示了在糖皮质激素抵抗的白血病细胞中，由于CASP 1和NLRP 3启动子的体细胞甲基化显著降低，caspase 1（CASP 1）及其激活剂NLRP 3的表达显著升高。CASP 1的过度表达导致糖皮质激素受体的裂解，减少糖皮质激素诱导的转录反应和增加糖皮质激素抵抗。在CASP 1过表达的ALL中，CASP 1的敲低或抑制显著增加糖皮质激素受体水平并减轻糖皮质激素抵抗。我们的研究结果建立了一种新的机制，通过这种机制，NLRP 3/CASP 1炎性小体调节糖皮质激素受体的细胞水平，并降低细胞对糖皮质激素的敏感性。对糖皮质激素转录反应的广泛影响表明，这种机制也可以改变糖皮质激素在其他疾病中的作用。
Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and leukemia cell resistant to glucocorticoids confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the sensitivity to prednisolone of primary leukemia cells from 444 newly diagnosed ALL patients, revealing significantly higher expression of caspase 1 (CASP1) and its activator NLRP3 in glucocorticoid resistant leukemia cells, due to significantly lower somatic methylation of CASP1 and NLRP3 promoters. Over-expression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished 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 glucocorticoid transcriptional response suggests this mechanism could also modify glucocorticoid effects in other diseases.
登录
查看更多内容
影响因子：
4.8
作者：
Garcia-Calvo, M;Peterson, EP;Thornberry, NA
通讯作者：
Thornberry, NA
影响因子：
20.3
作者：
Bachmann, PS;Gorman, R;Lock, RB
通讯作者：
Lock, RB
影响因子：
3.7
作者：
Bouligand J;Delemer B;Hecart AC;Meduri G;Viengchareun S;Amazit L;Trabado S;Fève B;Guiochon-Mantel A;Young J;Lombès M
通讯作者：
Lombès M
影响因子：
--
作者：
McKay, LI;Cidlowski, JA
通讯作者：
Cidlowski, JA
影响因子：
20.3
作者：
Hogan, Laura E.;Meyer, Julia A.;Carroll, William L.
通讯作者：
Carroll, William L.