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Leukemia-associated translocation products able to activate RAS modify PML and render cells sensitive to arsenic-induced apoptosis

Oncogene volume 22, pages 6900–6908 (2003)Cite this article

Abstract

Since the 19th century, arsenic (As2O3) has been used in the treatment of chronic myelogenous leukemia (CML) characterized by the t(9;22) translocation. As2O3 induces complete remissions in patients with acute promyelocytic leukemia. The response to As2O3 is genetically determined by the t(15;17)-or the t(9;22)-specific fusion proteins PML/RARα or BCR/ABL. The PML portion of PML/RARα is crucial for the sensitivity to As2O3. PML is nearly entirely contained in PML/RARα. PML is upregulated by oncogenic RAS in primary fibroblasts. The aberrant kinase activity of BCR/ABL leads to constitutive activation of RAS. Therefore, we hypothesized that BCR/ABL could increase sensitivity to As2O2-induced apoptosis by modifying PML expression. To disclose the mechanism of As2O3-induced apoptosis in PML/RARα- and BCR/ABL-expressing cells, we focused on the role of PML for As2O3-induced cell death. Here we report that (i) sensitivity to As2O3-induced apoptosis of U937 cells can be increased either by overexpression of PML, or by conditional expression of activated RAS; (ii) also the expression of the t(8;21)-related AML-1/ETO increased sensitivity to As2O3-induced apoptosis; (iii) both BCR/ABL and AML-1/ETO activated RAS and modified the PML expression pattern; (iv) the expression of either BCR/ABL or AML-1/ETO rendered U937 cells sensitive to interferon α-induced apoptosis. In summary, these data suggest a crucial role of factors able to upregulate PML for As2O2-induced cell death.

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Acknowledgements

Elena Puccetti and Tim Beissert were supported by a fellowship from ‘Deutsche José Carreras-Leukämie-Stiftung’ (DJCLS–Nat-99-1 and DJCLS-Nat-01-1, respectively). Martin Ruthardt is supported by grants from Deutsche Forschungsgemeinschaft (DFG RU 728/2-2), Dr Mildred-Scheel-Stiftung der Deutschen Krebshilfe e.V. (10-1916 Ru2) and Wilhelm-Sander-Stiftung (2001-026.1).

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  1. Elena Puccetti and Tim Beissert: EP and TB both should be considered as first authors

Authors and Affiliations

  1. Med. Klinik III/Abtl. Hämatologie, Johann Wolfgang Goethe-Universität, Frankfurt, D-60590, Germany

    Elena Puccetti, Tim Beissert, Saskia Güller, Jun E Li, Dieter Hoelzer, Oliver G Ottmann & Martin Ruthardt

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  1. Elena Puccetti
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Correspondence to Martin Ruthardt.

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Puccetti, E., Beissert, T., Güller, S. et al. Leukemia-associated translocation products able to activate RAS modify PML and render cells sensitive to arsenic-induced apoptosis. Oncogene 22, 6900–6908 (2003). https://doi.org/10.1038/sj.onc.1206747

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