Progressive chromatin rewiring by ETO2::GLIS2 revealed in a genome-edited human iPSC model of pediatric leukemia initiation

Pediatric acute myeloid leukemia frequently harbors fusion oncogenes associated with poor prognosis, including KMT2A, NUP98, and GLIS2 rearrangements. Although murine models have demonstrated their leukemogenic activities, the steps from a normal human cell to leukemic blasts remain unclear. Here, we precisely reproduced the inversion of chromosome 16 resulting in the ETO2::GLIS2 fusion in human induced pluripotent stem cells (iPSCs). iPSC-derived ETO2::GLIS2-expressing hematopoietic cells showed differentiation alterations in vitro and efficiently induced in vivo development of leukemia that closely phenocopied human acute megakaryoblastic leukemia (AMKL), reflected by flow cytometry and single-cell transcriptomes. Comparison of iPS-derived cells with patient-derived cells revealed altered chromatin accessibility at early and later bona fide leukemia stages, with aberrantly higher accessibility and expression of the osteogenic homeobox factor DLX3 that preceded increased accessibility to ETS factors. DLX3 overexpression in normal CD34+ cells increased accessibility to ETS motifs and reduced accessibility to GATA motifs. A DLX3 transcriptional module was globally enriched in both ETO2::GLIS2 AMKL and some aggressive pediatric osteosarcoma. Importantly, DLX3 knockout abrogated leukemia initiation in this ETO2::GLIS2 iPSC model. Collectively, the characterization of a novel human iPSC-derived AMKL model revealed that hijacking of the osteogenic homeobox transcription factor DLX3 is an essential early step in chromatin changes and leukemogenesis driven by the ETO2::GLIS2 fusion oncogene.

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Publication Details

Journal
Blood
Published
2024-12-10
DOI
https://doi.org/10.1182/blood.2024024505
Citations
2
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
0.91
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article

Progressive chromatin rewiring by ETO2::GLIS2 revealed in a genome-edited human iPSC model of pediatric leukemia initiation

Erika Brunet, Hana Raslová, Fabien Boudia, Thomas Mercher et al.
2 citations
Blood
Acute Myeloid Leukemia Research
0.91
article

Progressive chromatin rewiring by ETO2::GLIS2 revealed in a genome-edited human iPSC model of pediatric leukemia initiation

Erika Brunet, Hana Raslová, Fabien Boudia, Thomas Mercher, Brahim Arkoun, Juerg Schwaller, Nasséra Abermil, Julie Rivière, Zakia Aid, Antonin Marchais, Arnaud Petit, Salvatore Nicola Bertuccio, Verónica Alonso-Pérez, Marie Baille, Christophe Marzac, Hélène Lapillonne, Olivier Bernard, Cécile K. Lopez, Laura Anselmi, Muriel Gaudry, Françoise Pflumio, Nathalie Gaspar, Cyril Catelain, Patrick Gonin, Alexandre Eeckhoutte, Marie-Laure Arcangeli, Betty Leite, Audrey Naimo, Christophe Metereau, Elie Robert, Loélia Babin, Klaudia Galant, Alexia Regnault de Premesnil
article en
2 citations

Abstract

Pediatric acute myeloid leukemia frequently harbors fusion oncogenes associated with poor prognosis, including KMT2A, NUP98, and GLIS2 rearrangements. Although murine models have demonstrated their leukemogenic activities, the steps from a normal human cell to leukemic blasts remain unclear. Here, we precisely reproduced the inversion of chromosome 16 resulting in the ETO2::GLIS2 fusion in human induced pluripotent stem cells (iPSCs). iPSC-derived ETO2::GLIS2-expressing hematopoietic cells showed differentiation alterations in vitro and efficiently induced in vivo development of leukemia that closely phenocopied human acute megakaryoblastic leukemia (AMKL), reflected by flow cytometry and single-cell transcriptomes. Comparison of iPS-derived cells with patient-derived cells revealed altered chromatin accessibility at early and later bona fide leukemia stages, with aberrantly higher accessibility and expression of the osteogenic homeobox factor DLX3 that preceded increased accessibility to ETS factors. DLX3 overexpression in normal CD34+ cells increased accessibility to ETS motifs and reduced accessibility to GATA motifs. A DLX3 transcriptional module was globally enriched in both ETO2::GLIS2 AMKL and some aggressive pediatric osteosarcoma. Importantly, DLX3 knockout abrogated leukemia initiation in this ETO2::GLIS2 iPSC model. Collectively, the characterization of a novel human iPSC-derived AMKL model revealed that hijacking of the osteogenic homeobox transcription factor DLX3 is an essential early step in chromatin changes and leukemogenesis driven by the ETO2::GLIS2 fusion oncogene.

BloodVol. 145(14)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris Cité (FR), Wellcome/MRC Cambridge Stem Cell Institute (GB), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), University Hospital of Basel (CH), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), La Ligue Contre le Cancer (FR), CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR), Assistance Publique – Hôpitaux de Paris (FR), Hôpital Saint-Antoine (FR), Azienda USL di Bologna (IT), University Children’s Hospital Basel (CH), CEA Paris-Saclay (FR), Centre de Recherche Saint-Antoine (FR), Institut Carnot ARTS (FR), Institut des Maladies Génétiques Imagine (FR), Stabilité Génétique, Cellules Souches et Radiations (FR), University of Bologna (IT)
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Openalex Percentile: Top 21%
Acute Myeloid Leukemia Research
0.91
DOISourceOpenAlex
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