Ma Yun, Li Tingting, Feng Riyue, Guo Guijie, Pan Qidong, Li Jianning, Chen Jilong
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Sheng Wu Gong Cheng Xue Bao. 2020 Nov 25;36(11):2413-2423. doi: 10.13345/j.cjb.200015.
Human acute leukemia (AL) is a clonal malignancy with abnormal hematopoietic stem cells. Clinically, AL is very difficult to cure due to its sudden onset and short course of disease progression. Previous studies have shown that eukaryotic initiation factor 4B (eIF4B) plays a critical role in the development of chronic leukemia. However, the involvement of eIF4B in human acute leukemia is still largely unknown. Therefore, we studied eIF4B function and its regulatory mechanism in human acute leukemia. We found that phosphorylation levels of eIF4B in acute leukemia cells were significantly reduced in response to treatment with either LY294002 (PI3K inhibitor), AKTi (AKT inhibitor) or SMI-4A (Pim inhibitor). Co-treatment with inhibitors targeting JAK/STAT5/Pim and PI3K/AKT/mTOR signaling dramatically promoted apoptosis of acute leukemia cells by downregulating eIF4B phosphorylation. Furthermore, in vitro and in vivo functional experiments showed that eIF4B played an important anti-apoptosis role in the acute leukemia cells by regulating the expression of anti-apoptotic proteins Bcl-2 and Bcl-XL. In contrast, silencing eIF4B inhibited the growth of acute leukemia cells as engrafted tumors in nude mice. Taken together, our results indicate the synergistic role of JAK/STAT5/Pim and PI3K/AKT/mTOR signaling pathways in regulating eIF4B phosphorylation in acute leukemia, and highlight eIF4B as a candidate therapeutic target for treatment of acute leukemia.
人类急性白血病（AL）是一种造血干细胞异常的克隆性恶性肿瘤。临床上，由于其起病突然且病程进展迅速，AL很难治愈。先前的研究表明，真核生物起始因子4B（eIF4B）在慢性白血病的发展中起关键作用。然而，eIF4B在人类急性白血病中的作用仍 largely未知。因此，我们研究了eIF4B在人类急性白血病中的功能及其调控机制。我们发现，用LY294002（PI3K抑制剂）、AKTi（AKT抑制剂）或SMI-4A（Pim抑制剂）处理后，急性白血病细胞中eIF4B的磷酸化水平显著降低。联合使用靶向JAK/STAT5/Pim和PI3K/AKT/mTOR信号通路的抑制剂，通过下调eIF4B磷酸化，显著促进急性白血病细胞的凋亡。此外，体外和体内功能实验表明，eIF4B通过调节抗凋亡蛋白Bcl-2和Bcl-XL的表达，在急性白血病细胞中发挥重要的抗凋亡作用。相反，沉默eIF4B可抑制急性白血病细胞作为裸鼠移植瘤的生长。综上所述，我们的结果表明JAK/STAT5/Pim和PI3K/AKT/mTOR信号通路在调节急性白血病中eIF4B磷酸化方面具有协同作用，并突出了eIF4B作为急性白血病治疗候选靶点的地位。
