ZFIN ID: ZDB-PUB-180808-9
A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways
Piragyte, I., Clapes, T., Polyzou, A., Klein Geltink, R.I., Lefkopoulos, S., Yin, N., Cauchy, P., Curtis, J.D., Klaeylé, L., Langa, X., Beckmann, C.C.A., Wlodarski, M.W., Müller, P., Van Essen, D., Rambold, A., Kapp, F.G., Mione, M., Buescher, J.M., Pearce, E.L., Polyzos, A., Trompouki, E.
Date: 2018
Source: Nature communications 9: 3090 (Journal)
Registered Authors: Clapes, Thomas, Klaeylé, Lhéanna, Lefkopoulos, Stylianos, Mione, Marina, Müller, Patrick, Trompouki, Eirini
Keywords: none
MeSH Terms:
  • Animals
  • Autophagy
  • Cell Differentiation
  • Cell Proliferation
  • Cell Survival
  • Gene Expression Regulation*
  • Gene Expression Regulation, Leukemic
  • Hematopoiesis
  • Hematopoietic Stem Cells/metabolism*
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/physiology*
  • Humans
  • K562 Cells
  • Leukemia, Myeloid, Acute/genetics
  • Leukemia, Myeloid, Acute/metabolism*
  • Membrane Potential, Mitochondrial
  • PPAR gamma/metabolism
  • Phenotype
  • Reactive Oxygen Species/metabolism
  • Signal Transduction
  • Stem Cells/metabolism
  • Transcription Factors/genetics
  • Transcription Factors/physiology*
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/physiology*
PubMed: 30082823 Full text @ Nat. Commun.
FIGURES
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.
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