Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene– driven myeloid leukemia

Cécile K. Lopez, Esteve Noguera, Vaia Stavropoulou, Elie Robert, Zakia Aid, Paola Ballerini, Chrystèle Bilhou-Nabera, Hélène Lapillonne, Fabien Boudia, Cécile Thirant, Alexandre Fagnan, Marie Laure Arcangeli, Sarah J. Kinston, M’Boyba Diop, Bastien Job, Yann Lecluse, Erika Brunet, Loélia Babin, Jean Luc Villeval, Eric DelabesseAntoine H.F.M. Peters, William Vainchenker, Muriel Gaudry, Riccardo Masetti, Franco Locatelli, Sébastien Malinge, Claus Nerlov, Nathalie Droin, Camille Lobry, Isabelle Godin, Olivier A. Bernard, Berthold Göttgens, Arnaud Petit, Françoise Pflumio, Juerg Schwaller, Thomas Mercher

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1736-1753
Number of pages18
JournalCancer Discovery
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 2019

ASJC Scopus subject areas

  • Oncology

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    Lopez, C. K., Noguera, E., Stavropoulou, V., Robert, E., Aid, Z., Ballerini, P., Bilhou-Nabera, C., Lapillonne, H., Boudia, F., Thirant, C., Fagnan, A., Arcangeli, M. L., Kinston, S. J., Diop, MB., Job, B., Lecluse, Y., Brunet, E., Babin, L., Villeval, J. L., ... Mercher, T. (2019). Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene– driven myeloid leukemia. Cancer Discovery, 9(12), 1736-1753. https://doi.org/10.1158/2159-8290.CD-18-1463