急性白血病细胞中JAK/STAT5和PI3K/AKT信号通路对eIF4B的协同调控作用

Synergistic role of JAK/STAT5 and PI3K/AKT signaling pathways in regulating eIF4B in acute leukemia

摘要:

人类急性白血病 (Acute leukemia，AL) 是一类造血干细胞异常的克隆性恶性疾病。在临床上，急性白血病由于发病急、病程短等原因使其非常难以治愈。已有研究表明，慢性白血病的发生与真核转译起始因子4B (Eukaryotic initiation factor 4B，eIF4B) 的活化密切相关，但是其在急性白血病发生中的作用尚不明确。为了探究eIF4B在急性白血病发生中的作用及其机理，利用PI3K抑制剂LY294002、AKT抑制剂AKTi以及Pim抑制剂SMI-4A特异性地分别阻断JAK/STAT5/Pim和PI3K/AKT/mTOR信号通路，检测这两条信号通路下游共同靶标分子eIF4B的磷酸化水平。研究发现，阻断一条信号通路可明显降低eIF4B的磷酸化水平，而同时阻断两条信号通路能够更为显著地降低eIF4B活性并以一种协同作用的方式诱导细胞发生凋亡。进一步通过检测细胞凋亡和裸鼠致瘤实验，发现干扰eIF4B表达抑制了急性白血病细胞的存活及其在裸鼠体内的肿瘤形成。此外，敲低eIF4B可显著降低抗凋亡蛋白Bcl-2和Bcl-XL的蛋白表达水平。综上所述，在急性白血病细胞中eIF4B的活性受JAK/STAT5/Pim与PI3K/AKT/mTOR两条信号通路的共同调控，进而通过影响Bcl-2和Bcl-XL的表达发挥抗细胞凋亡作用，并促进急性白血病细胞介导的肿瘤生长。此研究有利于深入了解急性白血病的发生发展机制，为该病的靶向治疗提供理论指导。

Abstract:

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.