Acute myeloid leukemia (AML) is characterized by an increased proliferation and loss of differentiation of hematopoietic myeloid progenitors or precursors. Studies performed in AML-affected patients revealed a T cell deficiency characterized by a reduced thymic output and peripheral functional abnormalities. To assess for the thymus function during AML, we used an AML mouse model and showed a drastic thymic atrophy. We observed a massive loss among double (CD4+CD8+- DP) and single positive (CD4+/8+- SP) thymocytes. We assessed for the expression of different actors of cell death signalling pathways by RT-qPCR or Western blotting. When comparing leukemic to control mice, there was a significant increase in the expression of Mlkl gene, phosphorylated MLKL and RIPK3 proteins, and tumor necrosis factor (TNF)-alpha receptors 1 on DP and SP thymocytes. These findings revealed a necroptosis cell death which was also observed in vitro when using cultured wild-type thymocytes and recombinant TNF-alpha protein. Thus, we demonstrated that TNF-alpha plays a deleterious role in thymic function during AML by contributing to extensive thymocytes' death.

中文翻译：

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在急性髓系白血病小鼠模型中，肿瘤坏死因子-α/肿瘤坏死因子-α 受体 1 信号通路通过坏死性凋亡导致胸腺细胞死亡。

急性髓系白血病 (AML) 的特征是造血髓系祖细胞或前体细胞增殖增加和分化丧失。在受 AML 影响的患者中进行的研究揭示了 T 细胞缺陷，其特征是胸腺输出减少和外周功能异常。为了评估 AML 期间的胸腺功能，我们使用了 AML 小鼠模型，结果显示胸腺严重萎缩。我们观察到双阳性（CD4+CD8+- DP）和单阳性（CD4+/8+- SP）胸腺细胞大量损失。我们通过 RT-qPCR 或蛋白质印迹评估了细胞死亡信号通路不同参与者的表达。当将白血病小鼠与对照小鼠进行比较时，DP和SP胸腺细胞上的Mlkl基因、磷酸化MLKL和RIPK3蛋白以及肿瘤坏死因子(TNF)-α受体1的表达显着增加。这些发现揭示了坏死性细胞死亡，在体外使用培养的野生型胸腺细胞和重组 TNF-α 蛋白时也观察到了这种情况。因此，我们证明TNF-α通过导致大量胸腺细胞死亡，在AML期间的胸腺功能中发挥有害作用。