Unknown,Transcriptomics,Genomics,Proteomics

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Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene-driven myeloid leukemia - scRNAseq - 2


ABSTRACT: Paediatric cancers present specific genetic alterations, however the principles underlying their differences to adult cancers are yet unclear. Poor prognosis paediatric myeloid leukaemia fusion oncogenes represent clinically-relevant models to investigate age-specific tumorigenesis. Here, we established an inducible murine model to show that the ETO2-GLIS2 fusion induces both megakaryoblastic and myeloid leukaemia in a cellular and developmental stage-dependent manner, reproducing different age and phenotype associations observed in patients. The aggressive megakaryoblastic leukemia phenotype developed from haematopoietic stem cells and was associated with massive rewiring of master transcription factors activities (e.g. ERG, GATA and CEBPA). Switching off ETO2-GLIS2 expression in transformed cells restored some long-term haematopoietic stem cell potential. In contrast, targeting downstream progenitors was required for the myeloid phenotype. These data demonstrate that the promiscuity between HSC and megakaryocytic states and the ontogenic changes in the cellular architecture of the hematopoietic tissue controls paediatric and phenotype specificities in myeloid leukaemia.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Mus musculus

SUBMITTER: Thomas Mercher 

PROVIDER: E-MTAB-8360 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Lopez Cécile K CK   Noguera Esteve E   Stavropoulou Vaia V   Robert Elie E   Aid Zakia Z   Ballerini Paola P   Bilhou-Nabera Chrystèle C   Lapillonne Hélène H   Boudia Fabien F   Thirant Cécile C   Fagnan Alexandre A   Arcangeli Marie-Laure ML   Kinston Sarah J SJ   Diop M'Boyba M   Job Bastien B   Lecluse Yann Y   Brunet Erika E   Babin Loélia L   Villeval Jean Luc JL   Delabesse Eric E   Peters Antoine H F M AHFM   Vainchenker William W   Gaudry Muriel M   Masetti Riccardo R   Locatelli Franco F   Malinge Sébastien S   Nerlov Claus C   Droin Nathalie N   Lobry Camille C   Godin Isabelle I   Bernard Olivier A OA   Göttgens Berthold B   Petit Arnaud A   Pflumio Françoise F   Schwaller Juerg J   Mercher Thomas T  

Cancer discovery 20191029 12


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 <i>ETO2-GLIS2</i>, 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 <i>ETO2-GLIS2</i> expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in ad  ...[more]

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