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

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

  • Lopez CK INSERM U1170, Gustave Roussy, Villejuif, France.
  • Noguera E INSERM U1170, Gustave Roussy, Villejuif, France.
  • Stavropoulou V University Children's Hospital Beider Basel (UKBB) and Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Robert E INSERM U1170, Gustave Roussy, Villejuif, France.
  • Aid Z INSERM U1170, Gustave Roussy, Villejuif, France.
  • Ballerini P Hôpital Trousseau, AP-HP, Paris, France.
  • Bilhou-Nabera C Sorbonne Université, CRSA-Unité INSERM, AP-HP, Hôpital Trousseau, Paris, France.
  • Lapillonne H Hôpital Saint Antoine, AP-HP, Paris, France.
  • Boudia F INSERM U1170, Gustave Roussy, Villejuif, France.
  • Thirant C INSERM U1170, Gustave Roussy, Villejuif, France.
  • Fagnan A INSERM U1170, Gustave Roussy, Villejuif, France.
  • Arcangeli ML 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.
  • Kinston SJ Wellcome and MRC Cambridge Stem Cell Institute and the Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
  • Diop M Gustave Roussy, Villejuif, France.
  • Job B Gustave Roussy, Villejuif, France.
  • Lecluse Y Gustave Roussy, Villejuif, France.
  • Brunet E Genome Dynamics in the Immune System Laboratory, Institut Imagine, INSERM, Université Paris Descartes, Sorbonne Paris Cité, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
  • Babin L Genome Dynamics in the Immune System Laboratory, Institut Imagine, INSERM, Université Paris Descartes, Sorbonne Paris Cité, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
  • Villeval JL INSERM U1170, Gustave Roussy, Villejuif, France.
  • Delabesse E INSERM U1037, Team 16, Center of Research of Cancerology of Toulouse, Hematology Laboratory, IUCT-Oncopole, France.
  • Peters AHFM Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
  • Vainchenker W INSERM U1170, Gustave Roussy, Villejuif, France.
  • Gaudry M INSERM U1170, Gustave Roussy, Villejuif, France.
  • Masetti R Department of Pediatrics, "Lalla Seràgnoli," Hematology-Oncology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
  • Locatelli F Department of Pediatrics, Sapienza, University of Rome, Rome, Italy.
  • Malinge S INSERM U1170, Gustave Roussy, Villejuif, France.
  • Nerlov C MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Droin N INSERM U1170, Gustave Roussy, Villejuif, France.
  • Lobry C INSERM U1170, Gustave Roussy, Villejuif, France.
  • Godin I INSERM U1170, Gustave Roussy, Villejuif, France.
  • Bernard OA INSERM U1170, Gustave Roussy, Villejuif, France.
  • Göttgens B Wellcome and MRC Cambridge Stem Cell Institute and the Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
  • Petit A Hôpital Trousseau, AP-HP, Paris, France.
  • Pflumio F 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.
  • Schwaller J University Children's Hospital Beider Basel (UKBB) and Department of Biomedicine, University of Basel, Basel, Switzerland. thomas.mercher@inserm.fr j.schwaller@unibas.ch.
  • Mercher T INSERM U1170, Gustave Roussy, Villejuif, France. thomas.mercher@inserm.fr j.schwaller@unibas.ch.
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  • 2019-10-31
Published in:
  • Cancer discovery. - 2019
Adolescent
Age Factors
Animals
Child
Child, Preschool
Female
Humans
Infant
Leukemia, Myeloid, Acute
Mice
Neoplasm Transplantation
Oncogene Proteins, Fusion
Transcription Factors
Tumor Cells, Cultured
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/18498
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