Elsässer Annika, Franzen Michael, Kohlmann Alexander, Weisser Martin, Schnittger Susanne, Schoch Claudia, Reddy Venkateshwar A, Burel Sebastian, Zhang Dong-Er, Ueffing Marius, Tenen Daniel G, Hiddemann Wolfgang, Behre Gerhard
Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University Munich, Germany.
Oncogene. 2003 Aug 28;22(36):5646-57. doi: 10.1038/sj.onc.1206673.
Overexpression of proto-oncogene c-jun and constitutive activation of the Jun N-terminal kinase (JNK) signaling pathway have been implicated in the leukemic transformation process. However, c-jun expression and the role of the JNK signaling pathway have not been investigated in primary acute myeloid leukemia (AML) cells with frequently observed balanced rearrangements such as t(8;21). In the present study, we report elevated c-jun mRNA expression in AML patient bone marrow cells with t(8;21), t(15;17) or inv(16), and a high correlation in mRNA expression levels of AML1-ETO and c-jun within t(8;21)-positive AML patient cells. In myeloid U937 cells, c-jun mRNA and protein expression increase upon inducible expression of AML1-ETO. AML1-ETO transactivates the human c-jun promoter through the proximal activator protein (AP-1) site by activating the JNK pathway. Overexpression of JNK-inhibitor JIP-1 and chemical JNK inhibitors reduce the transactivation capacity of AML1-ETO on the c-jun promoter and the proapoptotic function of AML1-ETO in U937 cells. An autocrine mechanism involving granulocyte-colony stimulating factor (G-CSF) and G-CSF receptor (G-CSF-R) might participate in AML1-ETO mediated JNK-signaling, because AML1-ETO induces G-CSF and G-CSF-R expression, and G-CSF-R-neutralizing antibodies reduce AML1-ETO-induced JNK phosphorylation. These data suggest a model in which AML1-ETO induces proto-oncogene c-jun expression via the proximal AP-1 site of the c-jun promoter in a JNK-dependent manner.
原癌基因c-jun的过表达和Jun氨基末端激酶（JNK）信号通路的组成性激活与白血病转化过程有关。然而，c-jun的表达以及JNK信号通路在具有常见平衡重排如t(8;21)的原发性急性髓系白血病（AML）细胞中的作用尚未得到研究。在本研究中，我们报道了t(8;21)、t(15;17)或inv(16)的AML患者骨髓细胞中c-jun mRNA表达升高，并且在t(8;21)阳性AML患者细胞中AML1-ETO和c-jun的mRNA表达水平高度相关。在髓系U937细胞中，AML1-ETO的诱导性表达会使c-jun mRNA和蛋白质表达增加。AML1-ETO通过激活JNK通路，经近端激活蛋白（AP-1）位点反式激活人c-jun启动子。JNK抑制剂JIP-1的过表达和化学JNK抑制剂降低了AML1-ETO对c-jun启动子的反式激活能力以及AML1-ETO在U937细胞中的促凋亡功能。一种涉及粒细胞集落刺激因子（G-CSF）和G-CSF受体（G-CSF-R）的自分泌机制可能参与AML1-ETO介导的JNK信号传导，因为AML1-ETO诱导G-CSF和G-CSF-R表达，并且G-CSF-R中和抗体降低AML1-ETO诱导的JNK磷酸化。这些数据提示了一个模型，即AML1-ETO通过c-jun启动子的近端AP-1位点以JNK依赖的方式诱导原癌基因c-jun表达。
