2. Academic Validation
  3. Developmental interplay between transcriptional alterations and a targetable cytokine signaling dependency in pediatric ETO2::GLIS2 leukemia

Developmental interplay between transcriptional alterations and a targetable cytokine signaling dependency in pediatric ETO2::GLIS2 leukemia

  • Mol Cancer. 2024 Sep 20;23(1):204. doi: 10.1186/s12943-024-02110-y.
Verónica Alonso-Pérez # 1 2 3,  Klaudia Galant # 1 2 3,  Fabien Boudia # 4,  Elie Robert # 4,  Zakia Aid 4,  Laurent Renou 1 2 3,  Vilma Barroca 1 2 5,  Saryiami Devanand 1 2 5,  Loélia Babin 6,  Virginie Rouiller-Fabre 1 2,  Delphine Moison 1 2,  Didier Busso 1 2 7,  Guillaume Piton 1 2 7,  Christophe Metereau 4,  Nassera Abermil 8,  Paola Ballerini 9,  Pierre Hirsch 8,  Rima Haddad 1 2 3,  Jelena Martinovic 10,  Arnaud Petit 9,  Hélène Lapillonne 9,  Erika Brunet 6,  Thomas Mercher # 11 12,  Françoise Pflumio # 13 14 15 16
Affiliations

Affiliations

  • 1 Commissariat À L'Energie Atomique Et Aux Energies Alternatives (CEA), Université Paris Cité, Institut National de La Santé Et de La Recherche Médicale (INSERM), Stabilité Génétique Cellules Souches Et Radiations, Fontenay-Aux-Roses, F-92260, France.
  • 2 Université Paris-Saclay, INSERM, CEA, Stabilité Génétique Cellules Souches Et Radiations, Fontenay-Aux-Roses, F-92260, France.
  • 3 Laboratoire Des Cellules Souches Hématopoïétiques Et Des Leucémies, Équipe Labellisée Ligue Contre Le Cancer, Equipe Niche Et Cancer Dans L'Hématopoïèse, Unité Mixte de Recherche (UMR) 1274 INSERM, CEA, 18 route du panorama, Fontenay-Aux Roses, F-92265, France.
  • 4 INSERM U1170, Gustave Roussy, Université Paris-Saclay, PEDIAC Program, Equipe Labellisée Ligue Contre Le Cancer, Villejuif, France.
  • 5 Animal Experimentation Platform, IRCM, CEA, Fontenay-Aux-Roses, F-92260, France.
  • 6 Laboratory of theGenome Dynamics in the Immune System, Équipe Labellisée Ligue Contre Le Cancer, Université Paris Cité, Université Paris-Saclay, INSERM UMR 1163, Institut Imagine, Paris, France.
  • 7 Cigex Molecular Platform, IRCM, CEA, IBFJ, Fontenay-Aux-Roses, France.
  • 8 Centre de Recherche Saint-Antoine, CRSA, SIRIC CURAMUS, Hôpital Saint-Antoine, Service d'Hématologie Biologique, Sorbonne Université, 75012, Paris, France.
  • 9 Department of Pediatric Hematology-Oncology, Hôpital Armand Trousseau, AP-HP, Paris, France.
  • 10 Unit of Fetal Pathology, Hôpital Antoine Beclère, AP-HP, Clamart, France.
  • 11 INSERM U1170, Gustave Roussy, Université Paris-Saclay, PEDIAC Program, Equipe Labellisée Ligue Contre Le Cancer, Villejuif, France. thomas.mercher@gustaveroussy.fr.
  • 12 OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Paris, France. thomas.mercher@gustaveroussy.fr.
  • 13 Commissariat À L'Energie Atomique Et Aux Energies Alternatives (CEA), Université Paris Cité, Institut National de La Santé Et de La Recherche Médicale (INSERM), Stabilité Génétique Cellules Souches Et Radiations, Fontenay-Aux-Roses, F-92260, France. francoise.pflumio@cea.fr.
  • 14 Université Paris-Saclay, INSERM, CEA, Stabilité Génétique Cellules Souches Et Radiations, Fontenay-Aux-Roses, F-92260, France. francoise.pflumio@cea.fr.
  • 15 Laboratoire Des Cellules Souches Hématopoïétiques Et Des Leucémies, Équipe Labellisée Ligue Contre Le Cancer, Equipe Niche Et Cancer Dans L'Hématopoïèse, Unité Mixte de Recherche (UMR) 1274 INSERM, CEA, 18 route du panorama, Fontenay-Aux Roses, F-92265, France. francoise.pflumio@cea.fr.
  • 16 OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Paris, France. francoise.pflumio@cea.fr.
  • # Contributed equally.
PMID: 39304903 DOI: 10.1186/s12943-024-02110-y
Abstract

Background: Several fusion oncogenes showing a higher incidence in pediatric acute myeloid leukemia (AML) are associated with heterogeneous megakaryoblastic and other myeloid features. Here we addressed how developmental mechanisms influence human leukemogenesis by ETO2::GLIS2, associated with dismal prognosis.

Methods: We created novel ETO2::GLIS2 models of leukemogenesis through lentiviral transduction and CRISPR-Cas9 gene editing of human fetal and post-natal hematopoietic stem/progenitor cells (HSPCs), performed in-depth characterization of ETO2::GLIS2 transformed cells through multiple omics and compared them to patient samples. This led to a preclinical assay using patient-derived-xenograft models to test a combination of two clinically-relevant molecules.

Results: We showed that ETO2::GLIS2 expression in primary human fetal CD34+ hematopoietic cells led to more efficient in vivo leukemia development than expression in post-natal cells. Moreover, cord blood-derived leukemogenesis has a major dependency on the presence of human cytokines, including IL3 and SCF. Single cell transcriptomes revealed that this cytokine environment controlled two ETO2::GLIS2-transformed states that were also observed in primary patient cells. Importantly, this cytokine sensitivity may be therapeutically-exploited as combined MEK and BCL2 inhibition showed higher efficiency than individual molecules to reduce leukemia progression in vivo.

Conclusions: Our study uncovers an interplay between the cytokine milieu and transcriptional programs that extends a developmental window of permissiveness to transformation by the ETO2::GLIS2 AML fusion oncogene, controls the intratumoral cellular heterogeneity, and offers a ground-breaking therapeutical opportunity by a targeted combination strategy.

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