American Society of Hematology
Blood
,  том 145 ,  издание 14 ,  страницы 1510-1525

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

Fabien Boudia 1, 2, 3
, 
Marie Baille 1, 2, 3, 4
, 
Loelia Babin 5
, 
Loélia Babin 6
, 
Zakia Aid 1, 2, 7
, 
ROBERT ELIE 1, 2, 4
, 
Julie Rivière 1, 2, 4
, 
Klaudia Galant 8, 9
, 
Verónica Alonso-Pérez 9, 10
, 
Laura Anselmi 1, 4, 11
, 
Brahim Arkoun 1, 12, 13
, 
Nassera Abermil 14, 15
, 
Christophe Marzac 12, 16
, 
Salvatore Nicola Bertuccio 17, 18
, 
Alexia Regnault de Premesnil 4
, 
Alexia de Prémesnil 1, 3
, 
Cecile K. Lopez 19
, 
Cécile K. Lopez 20
, 
Alexandre Eeckhoutte 1, 2, 4
, 
Audrey Naimo 21, 22
, 
Betty Leite 12, 22
, 
Cyril Catelain 23, 24
, 
Christophe Metereau 1, 2, 4
, 
Patrick Gonin 25, 26
, 
Nathalie Gaspar 27, 28
, 
J Schwaller 29, 30
, 
Olivier A. Bernard 1, 2, 31
, 
Hana Raslova 13, 32
, 
Murielle Gaudry 1, 2, 33
, 
Antonin Marchais 4, 28
, 
Hélène Lapillonne 34, 35, 36
, 
Arnaud Petit 35, 36, 37, 38
, 
Françoise Pflumio 9, 38, 39
, 
Marie-Laure Arcangeli 1, 2, 33
, 
Erika Brunet 2, 3, 6
, 
T. Mercher 1, 2, 25, 38
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2Equipe labellisée Ligue Contre le Cancer, Paris, France | 
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CEA, Fontenay-aux-roses, France | 
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Saint-Antoine Hospital, Paris, France | 
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8Laboratoire d'Hématologie Biologique, Hôpital Universitaire Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France | 
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17Department of Pediatric Hematology and Oncology, Laboratory of Hematology, Armand Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France | 
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19OPALE Carnot Institute, Paris, France | 
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Тип публикации: Journal Article
Дата публикации: 2025-04-03
American Society of Hematology
scimago Q1
wos Q1
БС1
SJR: 5.823
CiteScore: 23.0
Impact factor: 23.1
ISSN: 00064971, 15280020
Краткое описание

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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Boudia F. et al. Progressive chromatin rewiring by ETO2::GLIS2 revealed in a human iPSC model of pediatric leukemia initiation // Blood. 2025. Vol. 145. No. 14. pp. 1510-1525.
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Boudia F. et al. Progressive chromatin rewiring by ETO2::GLIS2 revealed in a human iPSC model of pediatric leukemia initiation // Blood. 2025. Vol. 145. No. 14. pp. 1510-1525.
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TY - JOUR
DO - 10.1182/blood.2024024505
UR - https://ashpublications.org/blood/article/doi/10.1182/blood.2024024505/534446/Progressive-chromatin-rewiring-by-ETO2-GLIS2
TI - Progressive chromatin rewiring by ETO2::GLIS2 revealed in a human iPSC model of pediatric leukemia initiation
T2 - Blood
AU - Boudia, Fabien
AU - Baille, Marie
AU - Babin, Loelia
AU - Babin, Loélia
AU - Aid, Zakia
AU - ELIE, ROBERT
AU - Rivière, Julie
AU - Galant, Klaudia
AU - Alonso-Pérez, Verónica
AU - Anselmi, Laura
AU - Arkoun, Brahim
AU - Abermil, Nassera
AU - Marzac, Christophe
AU - Bertuccio, Salvatore Nicola
AU - Regnault de Premesnil, Alexia
AU - de Prémesnil, Alexia
AU - Lopez, Cecile K.
AU - Lopez, Cécile K.
AU - Eeckhoutte, Alexandre
AU - Naimo, Audrey
AU - Leite, Betty
AU - Catelain, Cyril
AU - Metereau, Christophe
AU - Gonin, Patrick
AU - Gaspar, Nathalie
AU - Schwaller, J
AU - Bernard, Olivier A.
AU - Raslova, Hana
AU - Gaudry, Murielle
AU - Marchais, Antonin
AU - Lapillonne, Hélène
AU - Petit, Arnaud
AU - Pflumio, Françoise
AU - Arcangeli, Marie-Laure
AU - Brunet, Erika
AU - Mercher, T.
PY - 2025
DA - 2025/04/03
PB - American Society of Hematology
SP - 1510-1525
IS - 14
VL - 145
PMID - 39656971
SN - 0006-4971
SN - 1528-0020
ER -
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@article{2025_Boudia,
author = {Fabien Boudia and Marie Baille and Loelia Babin and Loélia Babin and Zakia Aid and ROBERT ELIE and Julie Rivière and Klaudia Galant and Verónica Alonso-Pérez and Laura Anselmi and Brahim Arkoun and Nassera Abermil and Christophe Marzac and Salvatore Nicola Bertuccio and Alexia Regnault de Premesnil and Alexia de Prémesnil and Cecile K. Lopez and Cécile K. Lopez and Alexandre Eeckhoutte and Audrey Naimo and Betty Leite and Cyril Catelain and Christophe Metereau and Patrick Gonin and Nathalie Gaspar and J Schwaller and Olivier A. Bernard and Hana Raslova and Murielle Gaudry and Antonin Marchais and Hélène Lapillonne and Arnaud Petit and Françoise Pflumio and Marie-Laure Arcangeli and Erika Brunet and T. Mercher and others},
title = {Progressive chromatin rewiring by ETO2::GLIS2 revealed in a human iPSC model of pediatric leukemia initiation},
journal = {Blood},
year = {2025},
volume = {145},
publisher = {American Society of Hematology},
month = {apr},
url = {https://ashpublications.org/blood/article/doi/10.1182/blood.2024024505/534446/Progressive-chromatin-rewiring-by-ETO2-GLIS2},
number = {14},
pages = {1510--1525},
doi = {10.1182/blood.2024024505}
}
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Boudia, Fabien, et al. “Progressive chromatin rewiring by ETO2::GLIS2 revealed in a human iPSC model of pediatric leukemia initiation.” Blood, vol. 145, no. 14, Apr. 2025, pp. 1510-1525. https://ashpublications.org/blood/article/doi/10.1182/blood.2024024505/534446/Progressive-chromatin-rewiring-by-ETO2-GLIS2.
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