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Chronic myleproliferative neoplasms

Loss of HIF-1α accelerates murine FLT-3ITD-induced myeloproliferative neoplasia

Leukemia volume 29, pages 2366–2374 (2015)Cite this article

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Abstract

Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1α (HIF-1α) has a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs), as well as leukemia-initiating cells (LICs) of acute myeloid leukemia and chronic myeloid leukemia. We have investigated the effect of HIF-1α loss on the phenotype and biology of FLT-3ITD-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1α leads to an enhanced MPN phenotype reflected by an increased number of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF-1α loss is cell intrinsic as shown by transplantation into recipient mice. HSC loss and organ-specific changes in the number and percentage of long-term HSCs were the most pronounced effects on a cellular level after HIF-1α deletion. Furthermore, we found a metabolic hyperactivation of malignant cells in the spleen upon loss of HIF-1α. Some of our findings are in contrary to what has been previously described for the role of HIF-1α in other myeloid hematologic malignancies and question the potential of HIF-1α as a therapeutic target.

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Acknowledgements

We thank Dr D Gary Gilliland (University of Pennsylvania, Philadelphia, PA, USA) for kindly providing Flt-3ITD knock-in mice and Dr David Bryder (Lund University, Lund, Sweden) for helpful discussions and advice on flow cytometry. This work was supported by project grants from Barncancerfonden, Cancerfonden and SSF through the Hemato-Linné and StemTherapy consortium (Sweden) (to JC) and a postdoctoral grant from Barncancerfonden (Sweden) (to TV-H).

Author Contributions

TV-H designed the research, performed experiments, analyzed data, created figures and wrote the manuscript; DT performed experiments; JC conceived and supervised the project, designed the research and wrote the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden

    T Velasco-Hernandez & J Cammenga

  2. Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Skanes University Hospital, Lund, Sweden

    D Tornero

  3. Department of Hematology, Skanes University Hospital, Lund, Sweden

    J Cammenga

  4. Department of Hematology, Linköping University Hospital, Linköping, Sweden

    J Cammenga

  5. Institution for Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

    J Cammenga

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  1. T Velasco-Hernandez
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Correspondence to J Cammenga.

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Velasco-Hernandez, T., Tornero, D. & Cammenga, J. Loss of HIF-1α accelerates murine FLT-3ITD-induced myeloproliferative neoplasia. Leukemia 29, 2366–2374 (2015). https://doi.org/10.1038/leu.2015.156

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