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

• Published in: Molecular cancer Vol. 23; no. 1; pp. 204 - 24
• Main Authors: Alonso-Pérez, Verónica, Galant, Klaudia, Boudia, Fabien, Robert, Elie, Aid, Zakia, Renou, Laurent, Barroca, Vilma, Devanand, Saryiami, Babin, Loélia, Rouiller-Fabre, Virginie, Moison, Delphine, Busso, Didier, Piton, Guillaume, Metereau, Christophe, Abermil, Nassera, Ballerini, Paola, Hirsch, Pierre, Haddad, Rima, Martinovic, Jelena, Petit, Arnaud, Lapillonne, Hélène, Brunet, Erika, Mercher, Thomas, Pflumio, Françoise
• Format: Journal Article
• Language: English
• Published: London BioMed Central 20.09.2024; BioMed Central Ltd; BMC
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Child; Cytokines; Cytokines - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Leukemic; Genes; Genetic aspects; Genetic transcription; Hematopoietic Stem Cells - metabolism; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncology; Pediatrics; Signal Transduction; France
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-024-02110-y

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.