Institute for Immunology, Faculty of Medicine, TU Dresden, Dresden, Germany.
Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
Cancer Res. 2023 Sep 1;83(17):2858-2872. doi: 10.1158/0008-5472.CAN-22-3860.
Genome damage is a main driver of malignant transformation, but it also induces aberrant inflammation via the cGAS/STING DNA-sensing pathway. Activation of cGAS/STING can trigger cell death and senescence, thereby potentially eliminating genome-damaged cells and preventing against malignant transformation. Here, we report that defective ribonucleotide excision repair (RER) in the hematopoietic system caused genome instability with concomitant activation of the cGAS/STING axis and compromised hematopoietic stem cell function, ultimately resulting in leukemogenesis. Additional inactivation of cGAS, STING, or type I IFN signaling, however, had no detectable effect on blood cell generation and leukemia development in RER-deficient hematopoietic cells. In wild-type mice, hematopoiesis under steady-state conditions and in response to genome damage was not affected by loss of cGAS. Together, these data challenge a role of the cGAS/STING pathway in protecting the hematopoietic system against DNA damage and leukemic transformation.
Loss of cGAS/STING signaling does not impact DNA damage-driven leukemogenesis or alter steady-state, perturbed or malignant hematopoiesis, indicating that the cGAS/STING axis is not a crucial antioncogenic mechanism in the hematopoietic system. See related commentary by Zierhut, p. 2807.
基因组损伤是恶性转化的主要驱动因素，但它也通过 cGAS/STING DNA 感应途径引起异常炎症。cGAS/STING 的激活会触发细胞死亡和衰老，从而可能消除基因组损伤细胞并防止恶性转化。在这里，我们报告造血系统中缺陷的核糖核苷酸切除修复（RER）导致基因组不稳定，同时激活 cGAS/STING 轴并损害造血干细胞功能，最终导致白血病发生。然而，cGAS、STING 或 I 型 IFN 信号的额外失活对 RER 缺陷造血细胞中的血细胞生成和白血病发展没有明显影响。在野生型小鼠中，稳态条件下的造血和对基因组损伤的反应不受 cGAS 缺失的影响。总之，这些数据挑战了 cGAS/STING 途径在保护造血系统免受 DNA 损伤和白血病转化中的作用。
cGAS/STING 信号的丧失不会影响 DNA 损伤驱动的白血病发生或改变稳态、失调或恶性造血，表明 cGAS/STING 轴不是造血系统中的关键抗肿瘤机制。见 Zierhut 的相关评论，第 2807 页。
