The ROS/SUMO Axis Contributes to the Response of Acute Myeloid Leukemia Cells to Chemotherapeutic Drugs

Guillaume Bossis*, Jean Emmanuel Sarry, Chamseddine Kifagi, Marko Ristic, Estelle Saland, François Vergez, Tamara Salem, Héléna Boutzen, Hayeon Baik, Frédérique Brockly, Mireia Pelegrin, Tony Kaoma, Laurent Vallar, Christian Récher, Stéphane Manenti, Marc Piechaczyk

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    79 Citations (Scopus)

    Abstract

    Chemotherapeutic drugs used in the treatment of acute myeloid leukemias (AMLs) are thought to induce cancer cell death through the generation of DNA double-strand breaks. Here, we report that one of their early effects is the loss of conjugation of the ubiquitin-like protein SUMO from its targets via reactive oxygen species (ROS)-dependent inhibition of the SUMO-conjugating enzymes. Desumoylation regulates the expression of specific genes, such as the proapoptotic gene DDIT3, and helps induce apoptosis in chemosensitive AMLs. In contrast, chemotherapeutics do not activate the ROS/SUMO axis in chemoresistant cells. However, pro-oxidants or inhibition of the SUMO pathway by anacardic acid restores DDIT3 expression and apoptosis in chemoresistant cell lines and patient samples, including leukemic stem cells. Finally, inhibition of the SUMO pathway decreases tumor growth in mice xenografted with AML cells. Thus, targeting the ROS/SUMO axis might constitute a therapeutic strategy for AML patients resistant to conventional chemotherapies.

    Original languageEnglish
    Pages (from-to)1815-1823
    Number of pages9
    JournalCell Reports
    Volume7
    Issue number6
    DOIs
    Publication statusPublished - 26 Jun 2014

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