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.

中文翻译：

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儿科 ETO2::GLIS2 白血病转录改变与靶向细胞因子信号传导依赖性之间的发育相互作用


一些融合癌基因在儿童急性髓系白血病 (AML) 中发病率较高，与巨核细胞和其他髓系特征的异质性相关。在这里，我们探讨了发育机制如何通过 ETO2::GLIS2 影响人类白血病发生，并与不良预后相关。我们通过慢病毒转导和人类胎儿和产后造血干/祖细胞 (HSPC) 的 CRISPR-Cas9 基因编辑创建了新型 ETO2::GLIS2 白血病发生模型，并通过多个组学对 ETO2::GLIS2 转化细胞进行了深入表征并将它们与患者样本进行比较。这导致了使用患者来源的异种移植模型来测试两种临床相关分子的组合的临床前测定。我们发现，在原代人胎儿 CD34+ 造血细胞中表达 ETO2::GLIS2 比在出生后细胞中表达更有效地导致体内白血病的发展。此外，脐带血源性白血病的发生主要依赖于人类细胞因子的存在，包括 IL3 和 SCF。单细胞转录组显示，这种细胞因子环境控制着两种 ETO2::GLIS2 转化状态，这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以在治疗上利用，因为 MEK 和 BCL2 联合抑制显示出比单个分子更高的效率，可以减少体内白血病的进展。我们的研究揭示了细胞因子环境和转录程序之间的相互作用，延长了 ETO2::GLIS2 AML 融合癌基因转化的允许发育窗口，控制肿瘤内细胞异质性，并通过靶向组合策略提供突破性的治疗机会。