KEY TAKEAWAYS
- The study aimed to investigate the role of developmental mechanisms in the leukemogenic process induced by the ETO2::GLIS2 fusion oncogene in pediatric AML.
- Researchers noted that targeting cytokine signaling may offer a novel therapy for ETO2::GLIS2 pediatric AML.
Several fusion oncogenes exhibit a higher prevalence in pediatric acute myeloid leukemia (AML) and are linked to diverse megakaryoblastic and other myeloid characteristics.
Verónica Alonso-Pérez and the team aimed to explore how developmental mechanisms impact human leukemogenesis driven by the ETO2::GLIS2 fusion, which is correlated with a poor prognosis.
They performed an inclusive analysis by creating 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).
They conducted an in-depth characterization of the ETO2::GLIS2 transformed cells using multiple omics approaches and compared the findings to patient samples. This comprehensive analysis facilitated the development of a preclinical assay employing patient-derived xenograft models to evaluate a combination of 2 clinically relevant molecules.
About ETO2::GLIS2 expression in primary human fetal CD34+ hematopoietic cells demonstrated a greater efficiency in inducing in vivo leukemia development compared to expression in post-natal cells.
Additionally, cord blood-derived leukemogenesis exhibited a significant dependence on the presence of human cytokines, including IL3 and SCF. Single-cell transcriptome analyses revealed that this cytokine environment regulated 2 distinct ETO2::GLIS2-transformed states that were also observed in primary patient cells.
Notably, this cytokine sensitivity could be therapeutically exploited, as combined MEK and BCL2 inhibition proved more effective than individual agents in reducing leukemia progression in vivo.
The study concluded that the interplay between the cytokine milieu and transcriptional programs not only extends the developmental window for transformation by the ETO2::GLIS2 AML fusion oncogene but also regulates intratumoral cellular heterogeneity. This insight presents a groundbreaking therapeutic opportunity through a targeted combination strategy.
The study was funded by Enfants Cancer Santé (ECS), Société Française de Lutte Contre les Cancers et les Leucémies de l’Enfant et de l’Adolescent (SFCE, RAK22052LLA), Institut National Du Cancer (PLBIO-2018–169, CONECT-AML: Subvention INCA-ARC-LIGUE_11905, PEDIAC: INCA_15670, PEDIAMOD22-008), Ligue Contre le Cancer (LNCC, TM: Equipe labellisée; FP: Equipe labellisée), VAP was supported by INCA and ECS/SFCE, KG received a PhD fellowship from the French Ministry of Research and higher Education and from LNCC, Fondation supported ZA pour la Recherche Médicale (FRM-ING20150532273), OPALE Carnot institute and Gustave Roussy (PMS Crescendo). FB was supported by FRM (FDT202106012809) and Gustave Roussy Genomic Core Facility (Taxe apprentissage 2022 FABO). FP, AP and TM teams are part of the OPALE Carnot institute (Grant obtained in 2022) and the Paris Kids Cancer program. FP team is part of Institut Hospitalo-Universitaire THEMA-2.
Source: https://pubmed.ncbi.nlm.nih.gov/39304903/
Alonso-Pérez V, Galant K, Boudia F, et al. (2024). “Developmental interplay between transcriptional alterations and a targetable cytokine signaling dependency in pediatric ETO2::GLIS2 leukemia.” Mol Cancer. 2024;23(1):204. Published 2024 Sep 20. doi:10.1186/s12943-024-02110-y
