Progressive chromatin rewiring by ETO2::GLIS2 revealed in a genome-edited human iPSC model of pediatric leukemia initiation
Abstract
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.
Article Details
Authors (33)
Fabien Boudia
1Gustave Roussy, PEDIAC program, INSERM U1170, Université Paris-Saclay, Villejuif, France
Marie Baille
1Gustave Roussy, PEDIAC program, INSERM U1170, Université Paris-Saclay, Villejuif, France
Loelia Babin
Zakia Aid
1Gustave Roussy, PEDIAC program, INSERM U1170, Université Paris-Saclay, Villejuif, France
Elie Robert
1Gustave Roussy, PEDIAC program, INSERM U1170, Université Paris-Saclay, Villejuif, France
Julie Riviere
4INSERM, Gustave Roussy, Université Paris-Saclay, PEDIAC program, Villejuif, France
Klaudia Galant
5UMR-E008, Stabilité Génétique, Cellules Souches et Radiations, Team Niche and Cancer in Hematopoiesis, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université de Paris-Université Paris-Saclay, Fontenay-aux-Roses, France
Verónica Alonso-Pérez
5UMR-E008, Stabilité Génétique, Cellules Souches et Radiations, Team Niche and Cancer in Hematopoiesis, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université de Paris-Université Paris-Saclay, Fontenay-aux-Roses, France
Laura Anselmi
Brahim Arkoun
1Gustave Roussy, PEDIAC program, INSERM U1170, Université Paris-Saclay, Villejuif, France
Nassera Abermil
8Laboratoire d'Hématologie Biologique, Hôpital Universitaire Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France
Christophe Marzac
1Gustave Roussy, Villejuif, France
Salvatore Nicola Bertuccio
10IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Alexia de Prémesnil
1Gustave Roussy, PEDIAC program, INSERM U1170, Université Paris-Saclay, Villejuif, France
Cecile K. Lopez
Alexandre Eeckhoutte
2Gustave Roussy, la Recherche Médicale, Villejuif, France
Audrey Naimo
12Gustave Roussy, Genomic Platform, Université Paris-Saclay, Unité Mixte de Service AMMICA, INSERM US23, Centre National de la Recherche Scientifique UMS 3655, Villejuif, France
Betty Leite
12Gustave Roussy, Genomic Platform, Université Paris-Saclay, Unité Mixte de Service AMMICA, INSERM US23, Centre National de la Recherche Scientifique UMS 3655, Villejuif, France
Cyril Catelain
13Gustave Roussy, Plateforme Imagerie et Cytométrie, Université Paris-Saclay, Unité Mixte de Service AMMICA, INSERM US23, Centre National de la Recherche Scientifique UMS 3655, Villejuif, France
Christophe Metereau
1Gustave Roussy, PEDIAC program, INSERM U1170, Université Paris-Saclay, Villejuif, France
Patrick Gonin
14Gustave Roussy Cancer Center, Université Paris-Saclay, UMS AMMICA, Villejuif, France
Nathalie Gaspar
Jürg Schwaller
16University Children’s Hospital Beider Basel and Department of Biomedicine, University of Basel, Basel, Switzerland
Olivier A. Bernard
4Université Paris-Saclay, INSERM, Gustave Roussy, Dynamique Moléculaire de la Transformation Hématopoïétique, Villejuif, France
Hana Raslova
Muriel Gaudry
1Gustave Roussy, PEDIAC program, INSERM U1170, Université Paris-Saclay, Villejuif, France
Antonin Marchais
Hélène Lapillonne
3Hôpital Trousseau, Sorbonne Université, AP-HP, Département d'Hématologie Biologique, Paris, France
Arnaud Petit
20Department of Pediatric Hematology and Oncology, Armand-Trousseau Hospital Assistance Publique–Hôpitaux de Paris and Sorbonne University, Paris, France
Françoise Pflumio
5UMR-E008, Stabilité Génétique, Cellules Souches et Radiations, Team Niche and Cancer in Hematopoiesis, Commissariat à l'Energie Atomique et aux Energies Alternatives, Université de Paris-Université Paris-Saclay, Fontenay-aux-Roses, France
Marie-Laure Arcangeli
Erika Brunet
2Equipe labellisée Ligue Contre le Cancer, Paris, France
Thomas Mercher