Notch信号传导是哺乳动物和果蝇之间高度保守的通路，在多种生物过程中发挥着关键作用。果蝇已成为研究造血和白血病的强大模型。除晶体细胞外，果蝇淋巴腺皮质区 (CZ) / 中间区 (IZ) 细胞的 Notch 信号传导强度较弱。然而，淋巴腺CZ/IZ细胞和循环血细胞中Notch激活对造血稳态维持的影响尚不清楚。在这里，我们发现淋巴腺 CZ/IZ 细胞中的 Notch 激活诱导祖细胞过度分化。此外，Notch 激活通过 NFκB/Toll 信号传导激活和增加活性氧 (ROS) 促进片状细胞生成。此外，我们发现淋巴腺 CZ/IZ 细胞和循环血细胞中的 Notch 激活导致不依赖 caspase 的非自噬性细胞死亡。然而，晶体细胞自噬是通过上调 Hippo/Yki 途径 Diap1 靶基因的表达而激活的。此外，我们发现Notch激活可以减轻细胞因子风暴并提高Rasv12白血病模型果蝇的存活率。我们的研究揭示了健康果蝇中 Notch 激活引起的造血失调的各种机制以及 Notch 激活对白血病模型果蝇的治疗作用。版权所有 © 2024。由 Elsevier Ltd 出版。

Notch signaling is a highly conserved pathway between mammals and Drosophila and plays a key role in various biological processes. Drosophila has emerged as a powerful model for studying hematopoiesis and leukemia. In exception to crystal cells, the strength of Notch signaling in Drosophila lymph gland cortical zone (CZ) / intermediate zone (IZ) cells is weak. However, the influence of Notch activation in the lymph gland CZ/IZ cells and circulating hemocytes on hematopoietic homeostasis maintenance is unclear. Here, we showed that Notch activation in lymph gland CZ/IZ cells induced overdifferentiation of progenitors. Moreover, Notch activation promoted lamellocyte generation via NFκB/Toll signaling activation and increased reactive oxygen species (ROS). In addition, we found that Notch activation in lymph gland CZ/IZ cells and circulating hemocytes caused caspase-independent and nonautophagic cell death. However, crystal cell autophagy was activated by upregulation of the expression of the target gene of the Hippo/Yki pathway Diap1. Moreover, we showed that Notch activation could alleviate cytokine storms and improve the survival of Rasv12 leukemia model flies. Our study revealed the various mechanisms of hematopoietic dysregulation induced by Notch activation in healthy flies and the therapeutic effect of Notch activation on leukemia model flies.Copyright © 2024. Published by Elsevier Ltd.