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Cancer Discov. 2019 Dec;9(12):1736-1753. doi: 10.1158/2159-8290.CD-18-1463. Epub 2019 Oct 29.

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.

Author information

1
INSERM U1170, Gustave Roussy, Villejuif, France.
2
Gustave Roussy, Villejuif, France.
3
Université Paris-Saclay, Villejuif, France.
4
Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.
5
University Children's Hospital Beider Basel (UKBB) and Department of Biomedicine, University of Basel, Basel, Switzerland.
6
Hôpital Trousseau, AP-HP, Paris, France.
7
Sorbonne Université, CRSA-Unité INSERM, AP-HP, Hôpital Trousseau, Paris, France.
8
Hôpital Saint Antoine, AP-HP, Paris, France.
9
Université Paris Diderot, Paris, France.
10
Unité Mixte de Recherche 967 INSERM, CEA/DRF/IBFJ/IRCM/LSHL, Université Paris-Diderot-Université Paris-Sud, Equipe labellisée Association Recherche Contre le Cancer, Fontenay-aux-roses, France.
11
Wellcome and MRC Cambridge Stem Cell Institute and the Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
12
Genome Dynamics in the Immune System Laboratory, Institut Imagine, INSERM, Université Paris Descartes, Sorbonne Paris Cité, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
13
INSERM U1037, Team 16, Center of Research of Cancerology of Toulouse, Hematology Laboratory, IUCT-Oncopole, France.
14
Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
15
Faculty of Sciences, University of Basel, Basel, Switzerland.
16
Department of Pediatrics, "Lalla Seràgnoli," Hematology-Oncology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
17
Department of Pediatrics, Sapienza, University of Rome, Rome, Italy.
18
Hematology-Oncology-IRCCS Ospedale Bambino Gesù, Rome, Italy.
19
MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
20
University Children's Hospital Beider Basel (UKBB) and Department of Biomedicine, University of Basel, Basel, Switzerland. thomas.mercher@inserm.fr j.schwaller@unibas.ch.
21
INSERM U1170, Gustave Roussy, Villejuif, France. thomas.mercher@inserm.fr j.schwaller@unibas.ch.
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Contributed equally

Abstract

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631.

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