Tang Yanjuan, Halvarsson Camilla, Nordigården Amanda, Kumar Komal, Åhsberg Josefine, Rörby Emma, Wong Wan Man, Jönsson Jan-Ingvar
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Linköping Integrative Regenerative Medicine Centre, Linköping University, Linköping, Sweden.
Exp Hematol. 2015 Jul;43(7):554-64. doi: 10.1016/j.exphem.2015.04.007. Epub 2015 Apr 27.
The phosphatidylinositol 3-kinase/AKT pathway is an integral component of signaling involved in the development of many cancers, including myeloid leukemias such as chronic myeloid leukemia and acute myeloid leukemia (AML). Increased AKT1 activity is frequently seen in AML patients, providing leukemic cells with growth and survival promoting signals. An important aspect of AKT1 function is its involvement in cellular metabolism and energy production. Under some circumstances, strong activation of AKT1 increases oxidative stress, which can cause apoptosis when cells progressively build up excess free radicals. This has been described in hematopoietic cells overexpressing activated AKT1; however, whether this is true in cells coexpressing other genetic events involved in leukemia is not known. This prompted us to investigate the effect of constitutively active AKT1 (myristoylated AKT1) in hematopoietic progenitor cells expressing constitutively active signal transducer and activator of transcription 5, Fms-related tyrosine kinase 3-internal tandem duplication, or antiapoptotic B-cell lymphoma 2. Surprisingly, myristoylated AKT1 was incompatible with proliferation driven by both signal transducer and activator of transcription 5 and Fms-related tyrosine kinase 3-internal tandem duplication, which triggered cell cycle block and apoptosis. Moreover, transplantable cells of B-cell lymphoma 2-transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT1. This was linked to AKT1-mediated proapoptotic functions and not to impairment in homing to the bone marrow. Although cells expressing hyperactivated AKT1 displayed higher levels of reactive oxygen species both in vitro and in vivo, the addition of the antioxidant N-acetyl-L-cysteine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT1 activity is incompatible with growth- and survival-promoting ability of other activated genes in AML.
磷脂酰肌醇3激酶/AKT通路是许多癌症（包括慢性髓性白血病和急性髓性白血病（AML）等髓系白血病）发生发展过程中信号传导的一个重要组成部分。AML患者中经常可见AKT1活性增加，这为白血病细胞提供了促进生长和存活的信号。AKT1功能的一个重要方面是其参与细胞代谢和能量产生。在某些情况下，AKT1的强烈激活会增加氧化应激，当细胞逐渐积累过多自由基时可导致细胞凋亡。这已在过表达活化AKT1的造血细胞中得到描述；然而，在共表达其他与白血病相关的基因事件的细胞中是否也是如此尚不清楚。这促使我们研究组成型活性AKT1（肉豆蔻酰化AKT1）在表达组成型活性转录信号转导和激活因子5、Fms相关酪氨酸激酶3内部串联重复或抗凋亡B细胞淋巴瘤2的造血祖细胞中的作用。令人惊讶的是，肉豆蔻酰化AKT1与由转录信号转导和激活因子5以及Fms相关酪氨酸激酶3内部串联重复驱动的增殖不相容，这会引发细胞周期阻滞和凋亡。此外，当表达过度活化的AKT1时，B细胞淋巴瘤2转基因小鼠的可移植细胞在受体小鼠中的植入能力受损。这与AKT1介导的促凋亡功能有关，而不是与归巢至骨髓的能力受损有关。尽管在体外和体内表达过度活化AKT1的细胞均显示出较高水平的活性氧，但添加抗氧化剂N-乙酰-L-半胱氨酸可显著降低细胞凋亡。综上所述，结果表明组成型AKT1活性与AML中其他活化基因的促生长和存活能力不相容。
