Abstract

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.

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Acknowledgements

We gratefully acknowledge the patients and their parents who participated in this research. We are appreciative of the expert technical assistance of M. Roberts, Y. Chu, Y. Wang, M.A. Payton, J. Stukenborg, S. Salehy, M. Needham, M. Chung, N. Lenchik, M. Loyd and E. Walker. We thank J. Groff and E. Stevens for figure preparation assistance and C. Simmons for assistance with manuscript preparation. We thank D. Green for his scientific advice and discussion of the manuscript. We thank C. Stewart, G. Neale, J. Morris and K. Rakestraw for their technical advice and expertise. This work was supported in part by US National Institutes of Health (NIH) National Cancer Institute grant R37CA36401 (W.E.E., M.V.R. and C.-H.P.), US NIH National Institute of General Medical Sciences Pharmacogenomics Research Network grant U01GM92666 (M.V.R. and W.E.E.), US NIH grant F32CA141762 (S.W.P.) and an American Recovery and Reinvestment Act supplement, 3R37CA036401-26S1 (W.E.E.). This work was also supported by Cancer Center Support Grant CA21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

    • Gabriele Stocco

    Present address: Department of Life Sciences, University of Trieste, Trieste, Italy.

Affiliations

  1. Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Steven W Paugh
    • , Erik J Bonten
    • , Laura B Ramsey
    • , William E Thierfelder
    • , Lucas T Laudermilk
    • , J Robert McCorkle
    • , Kristine R Crews
    • , Gabriele Stocco
    • , Mark R Wilkinson
    • , Wenjian Yang
    • , Seth E Karol
    • , Christian A Fernandez
    • , Barthelemy Diouf
    • , Colton Smith
    • , J Kevin Hicks
    • , Alessandra Zanut
    • , Audrey Giordanengo
    • , Daniel Crona
    • , Joy J Bianchi
    • , Linda Holmfeldt
    • , Charles G Mullighan
    • , Sima Jeha
    • , Deepa Bhojwani
    • , Ching-Hon Pui
    • , Mary V Relling
    •  & William E Evans
  2. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Steven W Paugh
    • , Erik J Bonten
    • , Laura B Ramsey
    • , William E Thierfelder
    • , Lucas T Laudermilk
    • , John C Panetta
    • , J Robert McCorkle
    • , Kristine R Crews
    • , Gabriele Stocco
    • , Mark R Wilkinson
    • , Wenjian Yang
    • , Seth E Karol
    • , Christian A Fernandez
    • , Barthelemy Diouf
    • , Colton Smith
    • , J Kevin Hicks
    • , Alessandra Zanut
    • , Audrey Giordanengo
    • , Daniel Crona
    • , Joy J Bianchi
    • , Mary V Relling
    •  & William E Evans
  3. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.

    • Daniel Savic
    •  & Richard M Myers
  4. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Prajwal Gurung
    • , R K Subbarao Malireddi
    •  & Thirumala-Devi Kanneganti
  5. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Marcelo Actis
    • , Anand Mayasundari
    • , Jaeki Min
    •  & R Kiplin Guy
  6. High-Performance Computing Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • David R Coss
    •  & Antonio M Ferreira
  7. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Yiping Fan
  8. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Cheng Cheng
  9. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Seth E Karol
    • , Sima Jeha
    • , Deepa Bhojwani
    •  & Ching-Hon Pui
  10. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Linda Holmfeldt
    •  & Charles G Mullighan
  11. Division of Pediatric Oncology-Hematology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands.

    • Monique L den Boer
    •  & Rob Pieters
  12. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

    • Rob Pieters
  13. Centre for Rare Diseases and Personalized Medicine, University of Birmingham, Birmingham, UK.

    • Thomas L Dunwell
    •  & Farida Latif
  14. New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA.

    • William L Carroll

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Contributions

S.W.P., E.J.B., D.S., L.B.R., W.E.T., P.G., R.K.S.M., M.A., A.M., J.M., D.R.C., L.T.L., Y.F., R.K.G., T.-D.K., M.V.R. and W.E.E. designed experiments. C.-H.P., S.J., M.V.R. and W.E.E. designed clinical trials. S.W.P., E.J.B., D.S., L.B.R., W.E.T., P.G., R.K.S.M., M.A., A.M., D.R.C., L.T.L., Y.F., A.Z., A.G., D.C., J.J.B. and L.H. performed experiments. S.W.P., E.J.B., D.S., L.B.R., W.E.T. and W.E.E. wrote the manuscript (reviewed by all authors). S.W.P., E.J.B., D.S., L.B.R., W.E.T., D.R.C., L.T.L., J.C.P., J.R.M., Y.F., K.R.C., G.S., M.R.W., A.M.F., C.C., W.Y., S.E.K., C.A.F., B.D., C.S., J.K.H., A.Z., A.G., D.C., J.J.B., L.H., C.G.M., M.L.d.B., R.P., S.J., T.L.D., F.L., D.B., W.L.C., C.-H.P., R.M.M., R.K.G., T.-D.K., M.V.R. and W.E.E. analyzed data.

Competing interests

W.E.E., S.W.P. and E.J.B. are named as co-inventors on a pending patent application that relates to the subject matter of the article, which was filed by St. Jude Children's Research Hospital.

Corresponding author

Correspondence to William E Evans.

Integrated supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–8 and Supplementary Tables 1 and 5.

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    Supplementary Table 2

    Upregulated genes.

  2. 2.

    Supplementary Table 3

    Downregulated genes.

  3. 3.

    Supplementary Table 4

    Random unchanged genes.

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DOI

https://doi.org/10.1038/ng.3283

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