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.
Université Paris-Saclay, INSERM, CEA, Stabilité Génétique Cellules Souches Et Radiations, Fontenay-Aux-Roses, F-92260, France.
Mol Cancer. 2024 Sep 20;23(1):204. doi: 10.1186/s12943-024-02110-y.
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.
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.
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.
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.
在小儿急性髓系白血病（AML）中，几种融合癌基因的发生率较高，与异质性巨核细胞和其他髓样特征有关。在这里，我们通过 ETO2::GLIS2 解决了发育机制如何影响人类白血病发生的问题，该基因与预后不良有关。
我们通过慢病毒转导和 CRISPR-Cas9 基因编辑创建了新的 ETO2::GLIS2 白血病发生模型，对人类胎儿和出生后造血干/祖细胞（HSPCs）进行了深入的特征分析，通过多种组学比较了 ETO2::GLIS2 转化细胞，并将其与患者样本进行比较。这导致了一种使用患者衍生的异种移植模型的临床前测定，以测试两种临床相关分子的组合。
我们表明，ETO2::GLIS2 在原代人胎儿 CD34 造血细胞中的表达比在出生后细胞中的表达更有效地导致体内白血病的发展。此外，脐血衍生的白血病发生对人细胞因子（包括 IL3 和 SCF）的存在有很大的依赖性。单细胞转录组学揭示，这种细胞因子环境控制了两种 ETO2::GLIS2 转化状态，这些状态也在原代患者细胞中观察到。重要的是，这种细胞因子敏感性可能被治疗性地利用，因为 MEK 和 BCL2 的联合抑制比单个分子更有效地减少体内白血病的进展。
我们的研究揭示了细胞因子环境与转录程序之间的相互作用，这种相互作用扩展了 ETO2::GLIS2 AML 融合癌基因转化的可允许发育窗口，控制了肿瘤内细胞异质性，并通过靶向联合策略提供了一个开创性的治疗机会。
