Inducible expression of AML1-ETO fusion protein endows leukemic cells with susceptibility to extrinsic and intrinsic apoptosis
Inducible expression of AML1-ETO fusion protein endows leukemic cells with susceptibility to extrinsic and intrinsic apoptosis
复制标题
AML1-ETO融合蛋白的诱导表达赋予白血病细胞对外源性和内在性细胞凋亡的敏感性
DOI：
10.1038/sj.leu.2404218
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发表时间：
2006-06-01
期刊：
影响因子：
11.4
通讯作者：
Chen, G. -Q.
中科院分区：
文献类型：
--
作者：
Lu, Y.;Xu, Y. -B.;Chen, G. -Q.
AML 1-ETO是一种白血病相关融合蛋白，由急性髓性白血病中频繁发生的染色体易位t（8; 21）产生，在白血病细胞中显示出二分法功能，即生长停滞与分化阻滞。通过寡核苷酸芯片的分析，AML 1-ETO被证明可以调节一系列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AML 1-ETO表达对白血病U937细胞系凋亡的潜在影响。我们发现，AML 1-ETO显着稳定死亡受体Fas蛋白和增加促凋亡巴克除了减少Bcl-2的表达。因此，诱导型AML 1-ETO表达之后是较低程度的凋亡。特别是，AML 1-ETO赋予白血病细胞对抗Fas激动剂抗体、紫外线和喜树碱类似物NSC 606985诱导的凋亡的易感性，并增加caspase-3/8的活化。考虑到AML 1-ETO的促白血病作用不利于携带t（8; 21）易位的白血病的发生，必须克服它才能发挥其致白血病的潜能。补充这一预测的是，两个AML 1-ETO携带白血病细胞，Kasumi-1和SKNO-1，目前类似的敏感性与AML 1-ETO阴性白血病细胞的凋亡诱导。因此，对AML 1-ETO调控的白血病相关基因的遗传学和/或表观遗传学筛选值得探索，以了解AML 1-ETO诱导白血病发生的机制。
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.