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DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

View ORCID ProfileTim Kong, Angelo Brunelli Albertoni Laranjeira, Kangning Yang, Daniel A. C. Fisher, LaYow Yu, Anthony Z Wang, Marianna Ruzinova, Jared S. Fowles, Maggie J. Allen, Hamza Celik, Grant A. Challen, Sidong Huang, View ORCID ProfileStephen T. Oh
doi: https://doi.org/10.1101/2021.06.27.449656
Tim Kong
1Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Angelo Brunelli Albertoni Laranjeira
1Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Kangning Yang
2Department of Biochemistry, McGill University, Montreal, Quebec, Canada
3Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
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Daniel A. C. Fisher
1Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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LaYow Yu
1Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Anthony Z Wang
4Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, USA
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Marianna Ruzinova
5Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Jared S. Fowles
1Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Maggie J. Allen
1Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Hamza Celik
6Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Grant A. Challen
6Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Sidong Huang
2Department of Biochemistry, McGill University, Montreal, Quebec, Canada
3Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
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Stephen T. Oh
1Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
7Immunomonitoring Laboratory, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
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  • For correspondence: stoh@wustl.edu
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Abstract

Chronic myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed bulk transcriptome profiling accompanied by single cell RNA-sequencing on CD34+ stem/progenitor cells from serial patient samples obtained at the chronic MPN and sAML phases, and identified aberrantly increased expression of dual-specificity phosphatase 6 (DUSP6) underlying disease transformation. Genetic and pharmacologic targeting of DUSP6 led to inhibition of S6 and JAK/STAT signaling, resulting in potent suppression of cell proliferation, while also reducing inflammatory cytokine production in primary samples. Furthermore, ectopic DUSP6 expression augmented proliferation and mediated JAK2 inhibitor resistance, while DUSP6 inhibition reduced colony-forming potential of JAK2 inhibitor-persistent patient cells. Mechanistically, DUSP6 perturbation dampened S6 signaling via inhibition of RSK1, which we identified as a second indispensable candidate associated with poor clinical outcome. Lastly, DUSP6 inhibition potently suppressed disease development across Jak2 V617F and MPL W515L MPN mouse models, and sAML patient-derived xenografts. These findings underscore DUSP6 in driving disease transformation and therapeutic resistance, and highlight the DUSP6-RSK1 axis as a novel, druggable pathway in myeloid malignancies.

Competing Interest Statement

S.T.O. has served as a consultant for Kartos Therapeutics, CTI BioPharma, Celgene/Bristol Myers Squibb, Disc Medicine, Blueprint Medicines, PharmaEssentia, Constellation, Geron, Abbvie, Sierra Oncology, and Incyte. All other authors disclose no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 02, 2021.
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DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression
Tim Kong, Angelo Brunelli Albertoni Laranjeira, Kangning Yang, Daniel A. C. Fisher, LaYow Yu, Anthony Z Wang, Marianna Ruzinova, Jared S. Fowles, Maggie J. Allen, Hamza Celik, Grant A. Challen, Sidong Huang, Stephen T. Oh
bioRxiv 2021.06.27.449656; doi: https://doi.org/10.1101/2021.06.27.449656
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DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression
Tim Kong, Angelo Brunelli Albertoni Laranjeira, Kangning Yang, Daniel A. C. Fisher, LaYow Yu, Anthony Z Wang, Marianna Ruzinova, Jared S. Fowles, Maggie J. Allen, Hamza Celik, Grant A. Challen, Sidong Huang, Stephen T. Oh
bioRxiv 2021.06.27.449656; doi: https://doi.org/10.1101/2021.06.27.449656

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