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Animal Models

Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML

Leukemia volume 29, pages 2075–2085 (2015)Cite this article

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Abstract

Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells’ quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

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Acknowledgements

This work was supported by Project Grant no. 604303 from the National Health and Medical Research Council of Australia (to JPL and IGW) and additional support from the Mater Foundation. JPL and IGW are supported by a Senior Research Fellowship no. 1044091 and a Career Development Fellowship (no. 1033736) and FMH was supported by an Australian Based Biomedical Fellowship (no. 488821) from the National Health and Medical Research Council. We are indebted to Dr DJ Peet (University of Adelaide, Australia) who provided plasmid containing full-length human HIF-2α cDNA to Dr RB Lock (Children's Cancer Institute, Sydney, Australia) for providing B-ALL patient derived xenografts, and to Dr AW Boyd (Queensland Institute of Medical Research, Herston, Australia) for providing LK63 and REH cell lines.

Author Contributions

CEF, FMH, AB, JP, BN, VB, SM and DP performed the experiments. CEF, FMH, IGW, AB, JP, ACWZ, RDA, IL and JPL designed and planned the experiments, analyzed and discussed the results. RDA edited the manuscript. CEF, AB and JPL wrote the manuscript.

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Authors and Affiliations

  1. Stem Cell Biology Group, Mater Research Institute–University of Queensland, Woolloongabba, Queensland, Australia

    C E Forristal, F M Helwani, B Nowlan & J P Levesque

  2. Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia

    A L Brown, R J Powell, G A Engler, S M Diakiw, A C W Zannettino, S Martin, R J D'Andrea & I D Lewis

  3. Division of Health Sciences, School of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia, Australia

    A L Brown & R J D'Andrea

  4. Cancer and Stem Cells Group, Mater Research Institute–University of Queensland, Woolloongabba, Queensland, Australia

    I G Winkler, V Barbier & D Pattabiraman

  5. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    R J Powell

  6. School of Medical Sciences, Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia

    A C W Zannettino, S Martin & I D Lewis

  7. South Australian Health and Medical Research Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia

    A C W Zannettino

  8. School of Medicine, University of Queensland, Herston, Queensland, Australia

    J P Levesque

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  1. C E Forristal
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Correspondence to J P Levesque.

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Forristal, C., Brown, A., Helwani, F. et al. Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML. Leukemia 29, 2075–2085 (2015). https://doi.org/10.1038/leu.2015.102

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