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

• Published in: Nature communications 2018-08, Vol.9 (1), p.3090-17, Article 3090
• Main Authors: Piragyte, Indre, Clapes, Thomas, Polyzou, Aikaterini, Klein Geltink, Ramon I., Lefkopoulos, Stylianos, Yin, Na, Cauchy, Pierre, Curtis, Jonathan D., Klaeylé, Lhéanna, Langa, Xavier, Beckmann, Cora C. A., Wlodarski, Marcin W., Müller, Patrick, Van Essen, Dominic, Rambold, Angelika, Kapp, Friedrich G., Mione, Marina, Buescher, Joerg M., Pearce, Erika L., Polyzos, Alexander, Trompouki, Eirini
• Format: Article
• Language: English
• Subjects: 49/109; 49/15; 49/91; 59; 631/136/142; 631/136/232/2059; 631/337/572; 631/337/572/2102; 631/532/1542; 64; 64/116; 82/1; 96; 96/95; Acute myeloid leukemia; Animals; Autophagy; Biotechnology; Cell Differentiation; Cell Proliferation; Cell Survival; Cells (biology); Danio rerio; Differentiation; Electron transport; Electron transport chain; Gene expression; Gene Expression Regulation; Gene Expression Regulation, Leukemic; Hematopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Homeobox; Homeodomain Proteins - genetics; Homeodomain Proteins - physiology; Humanities and Social Sciences; Humans; K562 Cells; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Membrane Potential, Mitochondrial; Metabolism; multidisciplinary; Myeloid leukemia; Pharmacology; Phenotype; PPAR gamma - metabolism; Progenitor cells; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Signal Transduction; Stem Cells - metabolism; Transcription Factors - genetics; Transcription Factors - physiology; Viability; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05311-4

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. HLX transcription factor regulates haematopoietic stem and progenitor cell (HSPC) differentiation and is overexpressed in acute myeloid leukemia. Here the authors show that HLX overexpression leads to myeloid differentiation block in zebrafish and human HSPCs by direct regulation of metabolic pathways.