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

Autor: Piragyte I; Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Schänzlestraße 1, 79104, Freiburg, Germany., Clapes T; Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany., Polyzou A; Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Schänzlestraße 1, 79104, Freiburg, Germany., Klein Geltink RI; Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany., Lefkopoulos S; Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Schänzlestraße 1, 79104, Freiburg, Germany., Yin N; Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany., Cauchy P; Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany., Curtis JD; Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany., Klaeylé L; Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany., Langa X; Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012, Bern, Switzerland., Beckmann CCA; 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., Wlodarski MW; 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., Müller P; Systems Biology of Development Group, Friedrich Miescher Laboratory of the Max Planck Society, Max-Planck-Ring 9, 72076, Tübingen, Germany., Van Essen D; Institute for Research on Cancer and Aging Nice, 28 Ave de Valombrose, 06107, Nice Cedex 02, France., Rambold A; Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany.; Center for Chronic Immunodeficiency, Freiburg University Medical Center, 55 Hugstetter Street, 79106, Freiburg, Germany., Kapp FG; 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., Mione M; Centre for Integrative Biology, University of Trento, Via Sommarive, 9, 38123, Povo Trento, Italy., Buescher JM; Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany., Pearce EL; Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany., Polyzos A; Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Street, 115 27, Athens, Greece., Trompouki E; Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany. trompouki@ie-freiburg.mpg.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2018 Aug 06; Vol. 9 (1), pp. 3090. Date of Electronic Publication: 2018 Aug 06.
DOI: 10.1038/s41467-018-05311-4
Abstrakt: 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.
Databáze: MEDLINE