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A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways

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  • Indre Piragyte

    (Max Planck Institute of Immunobiology and Epigenetics
    University of Freiburg)

  • Thomas Clapes

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Aikaterini Polyzou

    (Max Planck Institute of Immunobiology and Epigenetics
    University of Freiburg)

  • Ramon I. Klein Geltink

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Stylianos Lefkopoulos

    (Max Planck Institute of Immunobiology and Epigenetics
    University of Freiburg)

  • Na Yin

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Pierre Cauchy

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Jonathan D. Curtis

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Lhéanna Klaeylé

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Xavier Langa

    (University of Bern)

  • Cora C. A. Beckmann

    (University of Freiburg)

  • Marcin W. Wlodarski

    (University of Freiburg)

  • Patrick Müller

    (Friedrich Miescher Laboratory of the Max Planck Society)

  • Dominic Van Essen

    (Institute for Research on Cancer and Aging Nice)

  • Angelika Rambold

    (Max Planck Institute of Immunobiology and Epigenetics
    Freiburg University Medical Center)

  • Friedrich G. Kapp

    (University of Freiburg)

  • Marina Mione

    (University of Trento)

  • Joerg M. Buescher

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Erika L. Pearce

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Alexander Polyzos

    (Biomedical Research Foundation of the Academy of Athens)

  • Eirini Trompouki

    (Max Planck Institute of Immunobiology and Epigenetics)

Abstract

The H2.0-like homeobox transcription factor (HLX) regulates hematopoietic differentiation and is overexpressed in Acute Myeloid Leukemia (AML), but the mechanisms underlying these functions remain unclear. We demonstrate here that HLX overexpression leads to a myeloid differentiation block both in zebrafish and human hematopoietic stem and progenitor cells (HSPCs). We show that HLX overexpression leads to downregulation of genes encoding electron transport chain (ETC) components and upregulation of PPARδ gene expression in zebrafish and human HSPCs. HLX overexpression also results in AMPK activation. Pharmacological modulation of PPARδ signaling relieves the HLX-induced myeloid differentiation block and rescues HSPC loss upon HLX knockdown but it has no effect on AML cell lines. In contrast, AMPK inhibition results in reduced viability of AML cell lines, but minimally affects myeloid progenitors. This newly described role of HLX in regulating the metabolic state of hematopoietic cells may have important therapeutic implications.

Suggested Citation

  • Indre Piragyte & Thomas Clapes & Aikaterini Polyzou & Ramon I. Klein Geltink & Stylianos Lefkopoulos & Na Yin & Pierre Cauchy & Jonathan D. Curtis & Lhéanna Klaeylé & Xavier Langa & Cora C. A. Beckman, 2018. "A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05311-4
    DOI: 10.1038/s41467-018-05311-4
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    Cited by:

    1. Ram Bhupal Reddy & Samanta S Khora & Amritha Suresh, 2019. "Molecular prognosticators in clinically and pathologically distinct cohorts of head and neck squamous cell carcinoma—A meta-analysis approach," PLOS ONE, Public Library of Science, vol. 14(7), pages 1-29, July.
    2. Nikolai Schleussner & Pierre Cauchy & Vedran Franke & Maciej Giefing & Oriol Fornes & Naveen Vankadari & Salam A. Assi & Mariantonia Costanza & Marc A. Weniger & Altuna Akalin & Ioannis Anagnostopoulo, 2023. "Transcriptional reprogramming by mutated IRF4 in lymphoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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