2. Academic Validation
  3. A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways

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

  • Nat Commun. 2018 Aug 6;9(1):3090. doi: 10.1038/s41467-018-05311-4.
Indre Piragyte 1 2,  Thomas Clapes 1,  Aikaterini Polyzou 1 2,  Ramon I Klein Geltink 3,  Stylianos Lefkopoulos 1 2,  Na Yin 1,  Pierre Cauchy 1,  Jonathan D Curtis 3,  Lhéanna Klaeylé 1,  Xavier Langa 4,  Cora C A Beckmann 5,  Marcin W Wlodarski 5,  Patrick Müller 6,  Dominic Van Essen 7,  Angelika Rambold 8 9,  Friedrich G Kapp 5,  Marina Mione 10,  Joerg M Buescher 3,  Erika L Pearce 3,  Alexander Polyzos 11,  Eirini Trompouki 12
Affiliations

Affiliations

  • 1 Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany.
  • 2 Faculty of Biology, University of Freiburg, Schänzlestraße 1, 79104, Freiburg, Germany.
  • 3 Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany.
  • 4 Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012, Bern, Switzerland.
  • 5 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Mathildenstr. 1, 79106, Freiburg, Germany.
  • 6 Systems Biology of Development Group, Friedrich Miescher Laboratory of the Max Planck Society, Max-Planck-Ring 9, 72076, Tübingen, Germany.
  • 7 Institute for Research on Cancer and Aging Nice, 28 Ave de Valombrose, 06107, Nice Cedex 02, France.
  • 8 Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany.
  • 9 Center for Chronic Immunodeficiency, Freiburg University Medical Center, 55 Hugstetter Street, 79106, Freiburg, Germany.
  • 10 Centre for Integrative Biology, University of Trento, Via Sommarive, 9, 38123, Povo Trento, Italy.
  • 11 Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Street, 115 27, Athens, Greece.
  • 12 Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany. [email protected].
PMID: 30082823 DOI: 10.1038/s41467-018-05311-4
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.

Figures
Products