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Acute Leukemias

Inducible expression of AML1-ETO fusion protein endows leukemic cells with susceptibility to extrinsic and intrinsic apoptosis

Leukemia volume 20, pages 987–993 (2006)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Zhu YS in Weill Medical College of Cornell University, New York for his careful editing assistance. We also deeply appreciate two anonymous reviewers for their thoughtful and serious evaluations on this work. Mrs Lu Y is a PhD candidate at Shanghai Jiaotong University School of Medicine, and this work is submitted in partial fulfillment of the requirement for her PhD. This work was supported in part by National Key Program (973) for Basic Research of China (NO2002CB512805) and National Natural Science Foundation of China (90408009 and 30500257). Grants from Science and Technology Committee of Shanghai (03XD14016, 05JC14032) should also be acknowledged.

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Authors and Affiliations

  1. 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

    Y Lu, Y-B Xu & G-Q Chen

  2. Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    T-T Yuan, M-G Song & G-Q Chen

  3. The Department of Medicine, University of Freiburg Medical Center, Freiburg, Germany

    M Lübbert & M Fliegauf

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  1. Y Lu
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Correspondence to G-Q Chen.

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Lu, Y., Xu, YB., Yuan, TT. et al. Inducible expression of AML1-ETO fusion protein endows leukemic cells with susceptibility to extrinsic and intrinsic apoptosis. Leukemia 20, 987–993 (2006). https://doi.org/10.1038/sj.leu.2404218

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