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Acute lymphoblastic leukemia

Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia

Leukemia volume 34, pages 2025–2037 (2020)Cite this article

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Abstract

Despite decades of clinical use, mechanisms of glucocorticoid resistance are poorly understood. We treated primary murine T lineage acute lymphoblastic leukemias (T-ALLs) with the glucocorticoid dexamethasone (DEX) alone and in combination with the pan-PI3 kinase inhibitor GDC-0941 and observed a robust response to DEX that was modestly enhanced by GDC-0941. Continuous in vivo treatment invariably resulted in outgrowth of drug-resistant clones, ~30% of which showed markedly reduced glucocorticoid receptor (GR) protein expression. A similar proportion of relapsed human T-ALLs also exhibited low GR protein levels. De novo or preexisting mutations in the gene encoding GR (Nr3c1) occurred in relapsed clones derived from multiple independent parental leukemias. CRISPR/Cas9 gene editing confirmed that loss of GR expression confers DEX resistance. Exposing drug-sensitive T-ALLs to DEX in vivo altered transcript levels of multiple genes, and this response was attenuated in relapsed T-ALLs. These data implicate reduced GR protein expression as a frequent cause of glucocorticoid resistance in T-ALL.

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Fig. 1: RIM-induced T-ALLs respond to dexamethasone as a single agent or in combination with GDC-0941 and exhibit intrinsic glucocorticoid resistance at relapse.
Fig. 2: Relapsed mouse and human T-ALLs show reduced glucocorticoid receptor protein expression, which is sufficient to confer dexamethasone resistance in vitro.
Fig. 3: Nr3c1 mutations in relapsed T-ALLs drive leukemia outgrowth in vivo and confer dexamethasone resistance in vitro.
Fig. 4: Relapsed T-ALLs with preexisting or acquired Nr3c1 mutations exhibit distinct evolutionary trajectories in response to dexamethasone treatment.
Fig. 5: Relapsed T-ALLs show attenuated transcriptional responses to in vivo dexamethasone treatment.

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Acknowledgements

We thank members of the Integrated Genomics Operation in the Marie-Josee and Henry R. Kravis Center for Molecular Oncology at the Memorial Sloan-Kettering Cancer Center, and the Genome Sequencing Lab at St. Jude Children’s Research Hospital for assistance with sequencing; the UCSF Biorepository and Tissue Biomarker Technology Core and the DF/HCC Research Pathology Cores at Harvard Medical School for performing immunohistochemistry analysis. This study was supported in part by the UCSF Helen Diller Family Comprehensive Cancer Center Laboratory for Cell Analysis Shared Resource Facility through a grant from the NIH (P30CA082103). We obtained KrasG12D mice from David Tuveson and Tyler Jacks, and Linda Wolff provided the MOL4070LTR retrovirus. This work was supported in part by National Institutes of Health awards R37 CA72614 (KS), R01 CA180037 (KS); P30 CA008748, U54 OD020355 (BST), R01 CA204749 (BST), and awards from the St. Baldrick’s Foundation (KS), the American Cancer Society (RSG-15-067-01-TBG) (KS), the Anna Fuller Fund, and the Robertson Foundation (BST). AMW was supported by a Postdoctoral Fellowship (PF-14-070-01-TBG) from the American Cancer Society including a supplement from the Hillcrest Committee, and an Alex’s Lemonade Stand Foundation Young Investigator Grant including support from Northwestern Mutual. KS is an American Cancer Society Research Professor (RP 10-078-01-TBE).

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Authors and Affiliations

  1. Department of Pediatrics, University of California, San Francisco, CA, USA

    Anica M. Wandler, Benjamin J. Huang, Kathryn Hayes, Hannah Yan, Lauren K. Meyer, Jasmine C. Wong & Kevin Shannon

  2. Department of Pathology, Brigham & Women’s Hospital, Boston, MA, USA

    Jeffrey W. Craig & Jon C. Aster

  3. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA

    Alessandro Scacchetti, Gabriela Monsalve & Keith Yamamoto

  4. Department of Translational Oncology, Genentech Inc., South San Francisco, CA, USA

    Monique Dail & Deepak Sampath

  5. Department of Medicine, University of Michigan, Ann Arbor, MI, USA

    Qing Li

  6. Department of Pathology, Boston Children’s Hospital, Boston, MA, USA

    Olga Weinberg

  7. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Robert P. Hasserjian

  8. Department of Laboratory Medicine, University of California, San Francisco, CA, USA

    Scott C. Kogan

  9. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Philip Jonsson & Barry S. Taylor

  10. Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Philip Jonsson & Barry S. Taylor

  11. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Joy Nakitandwe & James R. Downing

  12. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Jinghui Zhang

  13. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Barry S. Taylor

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  1. Anica M. Wandler
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Contributions

AMW, BJH, JWC, SCK, JCA, BST and KS designed experiments and analyzed data. AMW, JWC, KH, HY, LKM, AS, GM and JN performed experiments. BJH, PJ and BST performed bioinformatics analysis. MD, QL, JCW, OW, RPH, SCK, DS and JCA provided reagents. KY, JRD, JZ and MD provided conceptual advice. AMW and KS wrote the manuscript.

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Correspondence to Kevin Shannon.

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Deepak Sampath and Monique Dail were employees and shareholders of Genentech, Inc. when this work was performed. The remaining authors of this paper declare no financial interest related to this work.

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Wandler, A.M., Huang, B.J., Craig, J.W. et al. Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia. Leukemia 34, 2025–2037 (2020). https://doi.org/10.1038/s41375-020-0748-6

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