Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC, Canada.
Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC, Canada.
Cell Rep. 2023 Sep 26;42(9):113084. doi: 10.1016/j.celrep.2023.113084. Epub 2023 Sep 15.
Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We identify the dominant oncogenic properties of GLIS2 that trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of a number of BH3-only proteins, causing AMKL cell sensitivity to the BCL2 inhibitor navitoclax both in vitro and in vivo, suggesting a potential therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL.
儿童急性巨核细胞白血病（AMKL）是一种侵袭性血液癌，与治疗反应差和死亡率高有关。在这里，我们描述了 CBFA2T3-GLIS2 驱动的 AMKL 小鼠模型的发展，该模型重现了人类疾病的表型和转录特征。我们表明，发生在人类 AMKL 中的激活 Ras 突变增加了 CBF2AT3-GLIS2 驱动的 AMKL 的穿透性并降低了其潜伏期。CBFA2T3-GLIS2 和 GLIS2 调节相似的转录网络。我们确定了 GLIS2 的显性致癌特性，这些特性与致癌 Ras 共同引发 AMKL。我们发现 CBFA2T3-GLIS2 和 GLIS2 都改变了许多 BH3 仅蛋白的表达，导致 AMKL 细胞对 BCL2 抑制剂 navitoclax 在体外和体内均敏感，这为患有 CBFA2T3-GLIS2 驱动的 AMKL 的儿科患者提供了一种潜在的治疗选择。
