Cancer Research：微生物所在病毒诱导免疫细胞癌变机理研究中获新进展

小鼠白血病病毒（A-MuLV）可以诱导小鼠前B淋巴细胞发生癌变，进而导致小鼠白血病的发生，这类白血病与人类的Bcr-Abl阳性白血病的发生过程极为相似。因此，小鼠白血病病毒诱导免疫细胞癌变技术为我们研究人类白血病提供了良好的动物模型。A-MuLV携带的v-Abl与Bcr-Abl诱导白细胞癌变过程的信号转导通路存在许多共同点，例如 JAK/STAT信号通路持续活化，并且激活的JAK/STAT信号通路上调的Pim-1的表达在v-Abl、Bcr-Abl诱导的细胞癌变中发挥重要作用。Pim激酶可以通过调控多种下游分子的活性参与信号转导、细胞增殖、凋亡及肿瘤发生的分子调控。然而，Pim激酶促进v-Abl、Bcr-Abl介导的免疫细胞癌变的作用机制尚不很清楚。

中国科学院微生物研究所陈吉龙研究员领导的病毒感染与肿瘤发生机理研究组针对Pim激酶如何促进白血病病毒的v-Abl、人类Bcr-Abl癌基因介导的细胞癌变展开研究。通过细胞特异性标记和质谱分析，筛选鉴定到了Pim-1的下游分子真核转译起始因子eIF4B。体内、外实验均证实Pim-1、Pim-2可以调控eIF4B Ser406和Ser422位点磷酸化。eIF4B Ser422 位点的磷酸化对Pim激酶的干扰和抑制剂SMI-4a高度敏感。v-Abl、Bcr-Abl转化细胞中后eIF4B的表达与磷酸化呈现Abl激酶依赖形式。eIF4B、eIF4B Ser422模拟磷酸化突变体的表达可以减缓Pim激酶抑制剂SMI-4a引起的v-Abl、Bcr-Abl转化细胞的凋亡。不仅如此，eIF4B的干扰可以加快imatinib诱导的v-Abl、Bcr-Abl转化细胞的凋亡，且eIF4B干扰的Bcr-Abl转化细胞在裸鼠体内肿瘤生长受到抑制。此外，v-Abl、Bcr-Abl癌基因介导的eIF4B-knockdown转基因小鼠骨髓细胞转化效率明显降低。陈吉龙研究组通过一系列生物化学、分子生物学、转基因动物模型以及细胞生物学等实验证实了JAK/STAT信号通路调控的Pim激酶可以通过调控eIF4B Ser422的磷酸化促进v-Abl、Bcr-Abl介导的免疫细胞癌变。

此项研究揭示了Pim激酶促进白血病病毒感染介导免疫细胞癌变的机制。这些研究结果加深了我们对免疫细胞癌变机制的认识，为彻底阐明免疫细胞癌变的信号调控网络提供了帮助。该研究成果已在线发表于国际学术刊物Cancer Research上。

该项研究得到国家自然科学基金和“973”计划的支持。　

eIF4B phosphorylation by Pim kinases plays a critical role in cellular transformation by Abl oncogenes
Abstract
Alterations in translation occur in cancer cells but the precise pathogenic processes and mechanistic underpinnings are not well understood. In this study, we report that interactions between Pim family kinases and the translation initiation factor eIF4B are critical for Abl oncogenicity. Pim kinases Pim-1 and Pim-2 both directly phosphorylated eIF4B on Ser406 and Ser422. Phosphorylation of eIF4B on Ser422 was highly sensitive to pharmacological or RNAi-mediated inhibition of Pim kinases. Expression and phosphorylation of eIF4B relied upon Abl kinase activity in both v-Abl- and Bcr-Abl-expressing leukemic cells, based on their blockade by the Abl kinase inhibitor imatinib. Ectopic expression of phosphomimetic mutants of eIF4B conferred resistance to apoptosis by the Pim kinase inhibitor SMI-4a in Abl-transformed cells. In contrast, silencing eIF4B sensitized Abl transformed cells to imatinib-induced apoptosis and also inhibited their growth as engrafted tumors in nude mice. Extending these observations, we found that primary bone marrow cells derived from eIF4B-knockdown transgenic mice were less susceptible to Abl transformation, relative to cells from wild-type mice. Taken together, our results identify eIF4B as a critical substrate of Pim kinases in mediating the activity of Abl oncogenes, and they highlight eIF4B as a candidate therapeutic target for treatment of Abl-induced cancers.