Abstract

Approximately 80% of patients diagnosed with acute myeloid leukemia (AML) die as a consequence of failure to eradicate the tumor from the bone marrow microenvironment. We have recently shown that stroma-derived interleukin-8 (IL-8) promotes AML growth and survival in the bone marrow in response to AML-derived macrophage migration inhibitory factor (MIF). In the present study we show that high constitutive expression of MIF in AML blasts in the bone marrow is hypoxia-driven and, through knockdown of MIF, HIF1α and HIF2α, establish that hypoxia supports AML tumor proliferation through HIF1α signaling. In vivo targeting of leukemic cell HIF1α inhibits AML proliferation in the tumor microenvironment through transcriptional regulation of MIF, but inhibition of HIF2α had no measurable effect on AML blast survival. Functionally, targeted inhibition of MIF in vivo improves survival in models of AML. Here we present a mechanism linking HIF1α to a pro-tumoral chemokine factor signaling pathway and in doing so, we establish a potential strategy to target AML.

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Additional information

These authors contributed equally: Amina M. Abdul-Aziz and Manar S. Shafat.

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Acknowledgements

The authors wish to thank the Ministry of Higher Education and Scientific Research of the State of Libya, The Big C cancer charity (Norfolk, UK) and the National Institute for Health Research (UK) for funding and Professor Richard Ball, Dr Mark Wilkinson and Mr Iain Sheriffs, Norwich Biorepository (UK), for help with sample collection and storage. pCDH-luciferase-T2A-mCherry was kindly gifted from Prof. Dr. med. Irmela Jeremias, (Helmholtz Zentrum München, Munich, Germany).

Author contributions

AAA, MSS, KMB and SAR designed the research; AAA, CRM, REP and MSS, performed the research; SAR, CRM, SDR, and REP carried out in vivo work; DRE, ZZ, AC and KMB provided essential reagents and knowledge. AAA, MSS, KMB, and SAR wrote the paper.

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    Affiliations

    1. Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7UQ, United Kingdom

      • Amina M. Abdul-Aziz
      • , Manar S. Shafat
      • , Yu Sun
      • , Christopher R. Marlein
      • , Rachel E. Piddock
      • , Dylan R. Edwards
      • , Zhigang Zhou
      • , Kristian M. Bowles
      •  & Stuart A. Rushworth
    2. School of Biological Sciences, The University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom

      • Stephen D. Robinson
    3. Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Colney Lane, Norwich, NR4 7UY, United Kingdom

      • Angela Collins
      •  & Kristian M. Bowles

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    Correspondence to Stuart A. Rushworth.

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    https://doi.org/10.1038/s41388-018-0151-1