Lu Y, Xu Y-B, Yuan T-T, Song M-G, Lübbert M, Fliegauf M, Chen G-Q
The Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Leukemia. 2006 Jun;20(6):987-93. doi: 10.1038/sj.leu.2404218.
AML1-ETO, a leukemia-associated fusion protein generated by the frequently occurred chromosome translocation t(8;21) in acute myeloid leukemia, was shown to exert dichotomous functions in leukemic cells, that is, growth arrest versus differentiation block. By the analysis of oligonucleotide microarray, AML1-ETO was shown to modulate the expressions of an impressive array of pro- and anti-apoptotic genes. Here, we investigate potential effects of the ecdysone inducible AML1-ETO expression on apoptosis of leukemic U937 cell line. We show that AML1-ETO significantly stabilizes death receptor Fas protein and increases proapoptotic Bak in addition to reducing Bcl-2 expression. Accordingly, inducible AML1-ETO expression is followed by apoptosis to a lower degree. Especially, AML1-ETO endows leukemic cells with the susceptibility to anti-Fas agonist antibody, ultraviolet light and camptothecin analog NSC606985-induced apoptosis with increased activation of caspase-3/8. Considering that apoptosis-enhancing effect of AML1-ETO would not be favorable to the leukemogenesis harboring the t(8;21) translocation, it must be overcome to fulfill their leukemogenic potential. Complementary to this prediction is that two AML1-ETO-carrying leukemic cells, Kasumi-1 and SKNO-1, present similar sensitivity to apoptosis induction with AML1-ETO-negative leukemic cells. Therefore, genetic and/or epigenetic screenings of apoptosis-related genes modulated by AML1-ETO deserve to be explored for understanding the mechanisms of AML1-ETO-induced leukemogenesis.
AML1-ETO是一种在急性髓系白血病中由常见的染色体易位t(8;21)产生的白血病相关融合蛋白，已显示在白血病细胞中发挥双重功能，即生长停滞与分化阻滞。通过寡核苷酸微阵列分析，AML1-ETO被证明可调节一系列令人印象深刻的促凋亡和抗凋亡基因的表达。在此，我们研究蜕皮激素诱导的AML1-ETO表达对白血病U937细胞系凋亡的潜在影响。我们发现，AML1-ETO除了降低Bcl-2表达外，还能显著稳定死亡受体Fas蛋白并增加促凋亡蛋白Bak。因此，诱导性AML1-ETO表达后细胞凋亡程度较低。特别是，AML1-ETO使白血病细胞对抗Fas激动剂抗体、紫外线和喜树碱类似物NSC606985诱导的凋亡敏感，同时半胱天冬酶-3/8的激活增加。鉴于AML1-ETO的促凋亡作用不利于携带t(8;21)易位的白血病发生，必须克服这一作用才能实现其白血病发生潜能。与此预测相符的是，两个携带AML1-ETO的白血病细胞系Kasumi-1和SKNO-1与AML1-ETO阴性的白血病细胞对凋亡诱导具有相似的敏感性。因此，值得探索对AML1-ETO调节的凋亡相关基因进行遗传和/或表观遗传筛选，以了解AML1-ETO诱导白血病发生的机制。
