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

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. Beckmann, Marcin W. Wlodarski, Patrick Müller, Dominic Van Essen, Angelika Rambold, Friedrich G. Kapp, Marina Mione, Joerg M. Buescher, Erika L. Pearce, Alexander Polyzos and Eirini Trompouki ()
Additional contact information
Indre Piragyte: Max Planck Institute of Immunobiology and Epigenetics
Thomas Clapes: Max Planck Institute of Immunobiology and Epigenetics
Aikaterini Polyzou: Max Planck Institute of Immunobiology and Epigenetics
Ramon I. Klein Geltink: Max Planck Institute of Immunobiology and Epigenetics
Stylianos Lefkopoulos: Max Planck Institute of Immunobiology and Epigenetics
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
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

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05311-4

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