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Molecular targets for therapy

BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells

Leukemia volume 31, pages 678–687 (2017)Cite this article

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Abstract

Myeloproliferative neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling that responds to treatment with the JAK1 and 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary acute myeloid leukemia (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extraterminal) protein inhibitor (BETi), for example, JQ1, inhibits growth and induces apoptosis of cultured and primary, patient-derived (PD), post-MPN sAML blast progenitor cells. Reverse-phase protein array, mass-cytometry and Western analyses revealed that BETi treatment attenuated the protein expressions of c-MYC, p-STAT5, Bcl-xL, CDK4/6, PIM1 and IL-7R, whereas it concomitantly induced the levels of HEXIM1, p21 and BIM in the sAML cells. Co-treatment with BETi and ruxolitinib synergistically induced apoptosis of cultured and PD sAML cells, as well as significantly improved survival of immune-depleted mice engrafted with human sAML cells. Although BETi or heat shock protein 90 inhibitor (HSP90i) alone exerted lethal activity, cotreatment with BETi and HSP90i was synergistically lethal against the ruxolitinib-persister or ruxolitinib-resistant sAML cells. Collectively, these findings further support in vivo testing of BETi-based combinations with JAKi and HSP90i against post-MPN sAML cells.

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Acknowledgements

We thank the Functional Proteomics RPPA Core facility that is supported by the MD Anderson Cancer Center Support Grant 5P30 CA016672-40. The initial heatmaps were developed by the MD Anderson Cancer Center Department of Bioinformatics and Computational Biology, In Silico Solutions, Santeon and SRA International. This work was supported in part by the US National Cancer Institute (NCI; MD Anderson TCGA Genome Data Analysis Center) Grant Numbers CA143883 and CA083639, the Mary K Chapman Foundation and the Michael & Susan Dell Foundation (honoring Lorraine Dell). Additional support was also provided by CPRIT Metabolomics Core Facility Support Award RP120092 (CC), a pilot grant from Alkek Center for Molecular Discovery (CC). This research is supported in part by the MD Anderson Cancer Center Support Grant (P30 CA016672) and the MD Anderson Cancer Center Leukemia SPORE (P50 CA100632).

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Author notes

  1. D T Saenz and W Fiskus: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D T Saenz, W Fiskus, T Manshouri, S Krieger, B Sun, C P Mill, C DiNardo, N Pemmaraju, T Kadia, S Verstovsek & K N Bhalla

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    K Rajapakshe & C Coarfa

  3. Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S Parmar

  4. Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT, USA

    S Sharma

  5. Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA, USA

    P Qiu

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  1. D T Saenz
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Correspondence to K N Bhalla.

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Dr Pemmaraju serves on the scientific advisory board of Incyte Pharmaceuticals. He has also served as a consultant and received research funding from Novartis Pharmaceuticals. The other authors declare no conflict of interest.

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Saenz, D., Fiskus, W., Manshouri, T. et al. BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells. Leukemia 31, 678–687 (2017). https://doi.org/10.1038/leu.2016.260

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