NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.
СтатьяResearch Support, American Recovery and Reinvestment ActПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
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
Аннотация
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.