NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells
- Paugh S. W.
- Bonten E. J.
- Savic D.
- Ramsey L. B.
- Thierfelder W. E.
- Gurung P.
- Malireddi R. K. S.
- Actis M.
- Mayasundari A.
- Min J.
- Coss D. R.
- Laudermilk L. T.
- Panetta J. C.
- McCorkle J. R.
- Fan Y.
- Crews K. R.
- Stocco G.
- Wilkinson M. R.
- Ferreira A. M.
- Cheng C.
- Yang W.
- Karol S. E.
- Fernandez C. A.
- Diouf B.
- Smith C.
- Hicks J. K.
- Zanut A.
- Giordanengo A.
- Crona D.
- Bianchi J. J.
- Holmfeldt L.
- Mullighan C. G.
- Den Boer M. L.
- Pieters R.
- Jeha S.
- Dunwell T. L.
- Latif F.
- Bhojwani D.
- Carroll W. L.
- Pui C. -H.
- Myers R. M.
- Guy R. K.
- Kanneganti T. -D.
- Relling M. V.
- Evans W. E.
DOIAbstract
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. Knock...
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