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

Indre Piragyte,Lhéanna Klaeylé,Patrick Müller,Joerg M Buescher,Aikaterini Polyzou,Jonathan D Curtis,Alexander Polyzos,Xavier Langa,Dominic Van Essen,Thomas Clapes,Friedrich Kapp ,Na Yin,Marina Mione,Pierre Cauchy,Ramon I Klein Geltink,Angelika S Rambold ,Cora Beckmann ,Erika L Pearce,Marcin W Wlodarski,Stylianos Lefkopoulos,Eirini Trompouki

doi:10.1038/s41467-018-05311-4

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.

Highlights

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
To investigate the mechanisms underlying the role of HLX in promoting AML, we examined hematopoiesis in HLXoverexpressing zebrafish models
We chose to use human HLX in an effort to demonstrate conservation and translate our results into the human gene function. fli:hHLX overexpression led to increased specification of hematopoietic stem and progenitor cells (HSPCs) at 36 h post fertilization in the Aorta–Gonad–Mesonephros region as shown by runx[1] whole-mount in situ hybridization (WISH) (Fig. 1a and Supplementary Fig. 1a)

Summary

Introduction

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). 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. We use zebrafish, human hematopoietic stem and progenitor cells (HSPCs), and AML cell lines to explore the underlying mechanisms of HLX function during hematopoiesis. AMPK inhibition reduces viability of AML cell lines, but minimally affects primary cells This newly discovered link between HLX and metabolism could be a promising new avenue for treating hematological diseases

Methods

Results

Conclusion