ONTOGENIC CHANGES IN HEMATOPOIETIC HIERARCHY DETERMINES PEDIATRIC SPECIFICITY AND DISEASE PHENOTYPE IN FUSION ONCOGENE-DRIVEN MYELOID LEUKEMIA
Author(s): ,
Cécile Lopez
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Esteve Noguera
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Vaya Stavropoulou
Affiliations:
University Children’s Hospital Beider Basel (UKBB) a,Basel,Switzerland
,
Zakia Aid
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Paola Ballerini
Affiliations:
Hôpital Trousseau,Paris,France
,
Chrystèle Bilhou-Nabera
Affiliations:
Hôpital Trousseau,Paris,France
,
Helene Lapillonne
Affiliations:
Hôpital Trousseau,Paris,France
,
Cécile Thirant
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Alexandre Fagnan
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Marie-Laure Arcangeli
Affiliations:
CEA,Fontenay-aux-roses,France
,
Sarah Kinston
Affiliations:
University of Cambridge,Cambridge,United Kingdom
,
Mboyba Diop
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Yann Lecluse
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Erika Brunet
Affiliations:
Institut Imagine,Paris,France
,
Loelia Babin
Affiliations:
Institut Imagine,Paris,France
,
Jean Luc Villeval
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Eric Delabesse
Affiliations:
Center of Research of Cancerology of Toulouse,Toulouse,France
,
Antoine Peters
Affiliations:
FMI,Basel,Switzerland
,
William Vainchenker
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Muriel Gaudry
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Riccardo Masetti
Affiliations:
University of Bologna,Bologna,Italy
,
Franco Locatelli
Affiliations:
University of Pavia,Pavia,Italy
,
Sébastien Malinge
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Claus Nerlov
Affiliations:
University of Oxford,Oxford,United Kingdom
,
Camille Lobry
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Isabelle Godin
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Olivier Bernard
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
,
Berthold Göttgens
Affiliations:
University of Cambridge,Cambridge,United Kingdom
,
Arnaud Petit
Affiliations:
Hôpital Trousseau,Paris,France
,
Francoise Pflumio
Affiliations:
CEA,Fontenay-aux-roses,France
,
Juerg Schwaller
Affiliations:
University Children’s Hospital Beider Basel (UKBB) a,Basel,Switzerland
Thomas Mercher
Affiliations:
Gustave Roussy - INSERM,Villejuif,France
EHA Library. Lopez C. 06/16/19; 273256; LB2603
Cécile Lopez
Cécile Lopez
Contributions
Abstract

Abstract: LB2603

Type: Oral Presentation

Presentation during EHA24: On Sunday, June 16, 2019 from 11:45 - 12:00

Location: Hall 5

Background

Pediatric acute myeloblastic leukemia (AML) is an aggressive disease frequently driven by fusion oncogenes such as MLL, NUP98 fusions and ETO2-GLIS2 but the bases for the specific age and leukemia subtype associations are still unclear.

Aims

To test the hypothesis that changes in the hematopoietic hierarchy during development controls the phenotype (Acute megakaryoblastic leukemia: AMKL vs. other AML subtypes) and the aggressiveness of pediatric leukemia, we used ETO2-GLIS2 as a model and studied cellular and molecular determinants of aggressive AM(K)L.

Methods

We screened the ELAM02 pediatric AML cohort (276 patients) for ETO2-GLIS2 fusion and characterized the phenotypes of xenografts from 13 ETO2-GLIS2+ AML (8 AMKL and 5 AML). We engineered a doxycycline inducible ETO2-GLIS2 transgenic mouse model and analyzed the consequence of its expression in purified long-term hematopoietic stem cells (LT-HSC) and multipotent progenitors (MPP1-4) at different stages of development in vitro and in vivo. Molecular characterization of ETO2-GLIS2 expressing cells was done by ATACseq, single cell RNAseq and transcription factor activity inference.

Results

ETO2-GLIS2+ AMKL patients were diagnosed at a significantly younger age than other ETO2-GLIS2+ AML patients. In mice, ETO2-GLIS2 expression led to the development of lethal hematological malignancies that reproduced the different human AML phenotypes, including megakaryoblastic (4/19 mice) and immature/myeloid (15/19 mice) phenotypes. ETO2-GLIS2 expression in murine fetal HSC induced an aggressive megakaryoblastic leukemia in vivo, while its expression in adult HSC led to disease with a long latency. Expression in further committed MPP progenitors was required to induce a myeloid phenotype. ETO2-GLIS2 was sufficient to change chromatin conformation within 24 hours and supported an increased accessibility to ETS factors and reduced accessibility to GATA1. Single cell RNAseq in LT-HSC indicated that ETO2-GLIS2 rewires key transcription factors activity in a cell context- and developmental stage-dependent manner. Consistently, higher CEBPA activity was functionally required for ETO2-GLIS2-induced myeloid phenotype. Interestingly, switching off ETO2-GLIS2 expression in leukemic blasts derived from hematopoietic stem cells restored a capacity of differentiation into mature hematopoietic cells in vivo. Notably, expression of MLL-AF9 in fetal LT-HSC could also lead to lethal leukemia with clear megakaryoblastic features in vivo, showing that the ontogenic stage at which a fusion oncogene is activated determines the phenotype of pediatric AML.

Conclusion

By integrated analysis of patient samples and transgenic mouse models, we showed that aggressiveness and phenotypes in pediatric AML result from ontogeny-related differential susceptibility to transformation by several fusion oncogenes, which also provides a basis for the higher prevalence of AMKL in pediatric patients. These data also nourish the perspective that direct targeting of the fusion would alter leukemia maintenance and restore a multilineage differentiation potential.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Hematopoietic stem and progenitor cells, Ontogeny, Pediatric, Transcription factor

Abstract: LB2603

Type: Oral Presentation

Presentation during EHA24: On Sunday, June 16, 2019 from 11:45 - 12:00

Location: Hall 5

Background

Pediatric acute myeloblastic leukemia (AML) is an aggressive disease frequently driven by fusion oncogenes such as MLL, NUP98 fusions and ETO2-GLIS2 but the bases for the specific age and leukemia subtype associations are still unclear.

Aims

To test the hypothesis that changes in the hematopoietic hierarchy during development controls the phenotype (Acute megakaryoblastic leukemia: AMKL vs. other AML subtypes) and the aggressiveness of pediatric leukemia, we used ETO2-GLIS2 as a model and studied cellular and molecular determinants of aggressive AM(K)L.

Methods

We screened the ELAM02 pediatric AML cohort (276 patients) for ETO2-GLIS2 fusion and characterized the phenotypes of xenografts from 13 ETO2-GLIS2+ AML (8 AMKL and 5 AML). We engineered a doxycycline inducible ETO2-GLIS2 transgenic mouse model and analyzed the consequence of its expression in purified long-term hematopoietic stem cells (LT-HSC) and multipotent progenitors (MPP1-4) at different stages of development in vitro and in vivo. Molecular characterization of ETO2-GLIS2 expressing cells was done by ATACseq, single cell RNAseq and transcription factor activity inference.

Results

ETO2-GLIS2+ AMKL patients were diagnosed at a significantly younger age than other ETO2-GLIS2+ AML patients. In mice, ETO2-GLIS2 expression led to the development of lethal hematological malignancies that reproduced the different human AML phenotypes, including megakaryoblastic (4/19 mice) and immature/myeloid (15/19 mice) phenotypes. ETO2-GLIS2 expression in murine fetal HSC induced an aggressive megakaryoblastic leukemia in vivo, while its expression in adult HSC led to disease with a long latency. Expression in further committed MPP progenitors was required to induce a myeloid phenotype. ETO2-GLIS2 was sufficient to change chromatin conformation within 24 hours and supported an increased accessibility to ETS factors and reduced accessibility to GATA1. Single cell RNAseq in LT-HSC indicated that ETO2-GLIS2 rewires key transcription factors activity in a cell context- and developmental stage-dependent manner. Consistently, higher CEBPA activity was functionally required for ETO2-GLIS2-induced myeloid phenotype. Interestingly, switching off ETO2-GLIS2 expression in leukemic blasts derived from hematopoietic stem cells restored a capacity of differentiation into mature hematopoietic cells in vivo. Notably, expression of MLL-AF9 in fetal LT-HSC could also lead to lethal leukemia with clear megakaryoblastic features in vivo, showing that the ontogenic stage at which a fusion oncogene is activated determines the phenotype of pediatric AML.

Conclusion

By integrated analysis of patient samples and transgenic mouse models, we showed that aggressiveness and phenotypes in pediatric AML result from ontogeny-related differential susceptibility to transformation by several fusion oncogenes, which also provides a basis for the higher prevalence of AMKL in pediatric patients. These data also nourish the perspective that direct targeting of the fusion would alter leukemia maintenance and restore a multilineage differentiation potential.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Hematopoietic stem and progenitor cells, Ontogeny, Pediatric, Transcription factor

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