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Chronic myeloproliferative neoplasms

Hypoxia-inducible factor 1 (HIF-1) is a new therapeutic target in JAK2V617F-positive myeloproliferative neoplasms

Leukemia volume 34, pages 1062–1074 (2020)Cite this article

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Abstract

Classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic malignancies including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The JAK2V617F mutation plays a central role in these disorders and can be found in 90% of PV and ~50–60% of ET and PMF. Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of the response to decreased oxygen levels. We demonstrate the impact of pharmacological inhibition and shRNA-mediated knockdown (KD) of HIF-1α in JAK2V617F-positive cells. Inhibition of HIF-1 binding to hypoxia response elements (HREs) with echinomycin, verified by ChIP, impaired growth and survival by inducing apoptosis and cell cycle arrest in Jak2V617F-positive 32D cells, but not Jak2WT controls. Echinomycin selectively abrogated clonogenic growth of JAK2V617F cells and decreased growth, survival, and colony formation of bone marrow and peripheral blood mononuclear cells and iPS cell-derived progenitor cells from JAK2V617F-positive patients, while cells from healthy donors were unaffected. We identified HIF-1 target genes involved in the Warburg effect as a possible underlying mechanism, with increased expression of Pdk1, Glut1, and others. That was underlined by transcriptome analysis of primary patient samples. Collectively, our data show that HIF-1 is a new potential therapeutic target in JAK2V617F-positive MPN.

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Acknowledgements

This work was supported by the Genomics Facility, a core facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University. This work was supported by the Core Facility Flow Cytometry, a Core Facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University. This study was supported by a research grant from the German Research Foundation (DFG KO2155/6–1) to SK, from the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University (O3–3) and by START grant by the Faculty of Medicine in Aachen to DG. Biomaterial samples were provided by the RWTH centralized Biomaterial Bank Aachen (RWTH cBMB, Aachen, Germany) in accordance with the regulations of the biomaterial bank and the approval of the ethics committee of the medical faculty, RWTH Aachen. The Kranc laboratory is funded by Cancer Research UK (Senior Fellowship and Programme Grant), Medical Research Council, The Barts Charity, Bloodwise, and the Kay Kendall Leukaemia Fund. The pMSCV-IRES-GFP plasmids containing Jak2WT or Jak2V617F were a kind gift from the lab of Dr. Gary Gilliland. Parts of this work were part of the PhD thesis of JB and the bachelor’s thesis of AH.

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Authors and Affiliations

  1. Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    Julian Baumeister, Nicolas Chatain, Annika Hubrich, Lijuan Han, Caroline Küstermann, Tim H. Brümmendorf, Steffen Koschmieder & Deniz Gezer

  2. Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany

    Tiago Maié, Ivan G. Costa & Andreas Schuppert

  3. Interdisciplinary Center for Clinical Research Aachen, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    Bernd Denecke

  4. Institute of Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany

    Caroline Küstermann, Stephanie Sontag, Kristin Seré & Martin Zenke

  5. Institute for Transfusion Medicine, RWTH Aachen University Medical School, Aachen, Germany

    Klaus Strathmann

  6. Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK

    Kamil R. Kranc

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  1. Julian Baumeister
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Conflict of interest

SK reports advisory board activity for Pfizer, Incyte/Ariad, Novartis, AOP Pharma, BMS, CTI, Roche, Baxalta, Sanofi, honoraria from Novartis, BMS, Pfizer, Incyte/Ariad, Shire, Roche, AOP Pharma, Janssen, research funding from Novartis Foundation, BMS, Novartis, and other financial disclosures (i.e., travel support) from Alexion, Novartis, BMS, Incyte/Ariad, AOP Pharma, Baxalta, CTI, Pfizer, Sanofi, Celgene, Shire, and Janssen. THB reports consultancy from Pfizer, Novartis, Janssen, Merck, Incyte/Ariad and research funding from Pfizer and Novartis. DG reports advisory board activity for AMGEN. The remaining authors declare that they have no conflict of interest.

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Baumeister, J., Chatain, N., Hubrich, A. et al. Hypoxia-inducible factor 1 (HIF-1) is a new therapeutic target in JAK2V617F-positive myeloproliferative neoplasms. Leukemia 34, 1062–1074 (2020). https://doi.org/10.1038/s41375-019-0629-z

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