Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Mol Cancer Res. 2019 Jul;17(7):1450-1458. doi: 10.1158/1541-7786.MCR-19-0002. Epub 2019 Mar 22.
Hyperactive oncogenic Myc stimulates protein synthesis that induces the unfolded protein response, which requires the function of the eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Activated PERK acts to limit mRNA translation, enable proper protein folding, and restore the homeostasis in the endoplasmic reticulum. Given that Myc activation contributes to many types of lymphoid and myeloid human leukemias, we used a mouse model to examine the importance of PERK in development and progression of Myc-induced leukemias. We found that genetic ablation of does not suppress the generation of the leukemic cells in the bone marrow. However, the cell-autonomous deficiency restricts the dissemination of leukemic cells into peripheral blood, lymph nodes, and vital peripheral organs. Whereas the loss of the IFNAR1 chain of type I IFN receptor stimulated leukemia, ablation did not stabilize IFNAR1, suggesting that PERK stimulates the leukemic cells' dissemination in an IFNAR1-independent manner. We discuss the rationale for using PERK inhibitors against Myc-driven leukemias. IMPLICATIONS: The role of PERK in dissemination of Myc-induced leukemic cells demonstrated in this study argues for the use of PERK inhibitors against leukemia progression.
过表达的致癌 Myc 刺激蛋白质合成，从而诱导未折叠蛋白反应，这需要真核翻译起始因子 2-α 激酶 3（也称为蛋白激酶 R（PKR）样内质网激酶（PERK））的功能。激活的 PERK 作用是限制 mRNA 翻译、促进适当的蛋白质折叠，并恢复内质网的内稳态。鉴于 Myc 的激活有助于多种类型的淋巴样和髓样人类白血病，我们使用小鼠模型来研究 PERK 在 Myc 诱导的白血病发展和进展中的重要性。我们发现，PERK 的基因缺失并不能抑制骨髓中白血病细胞的产生。然而，细胞自主的 PERK 缺失限制了白血病细胞向外周血、淋巴结和重要的外周器官的扩散。虽然 I 型 IFN 受体的 IFNAR1 链缺失会刺激白血病，但 PERK 的缺失并没有稳定 IFNAR1，这表明 PERK 以 IFNAR1 非依赖性的方式刺激白血病细胞的扩散。我们讨论了使用 PERK 抑制剂对抗 Myc 驱动的白血病的原理。意义：本研究中 PERK 在 Myc 诱导的白血病细胞扩散中的作用表明，PERK 抑制剂可用于对抗白血病的进展。
