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

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 z...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078963/
https://www.ncbi.nlm.nih.gov/pubmed/30082823
http://dx.doi.org/10.1038/s41467-018-05311-4
Descripción
Sumario: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.