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

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. [Display omitted] •Chemotherapeutic drugs induce ROS-dependent desumoylation in chemosensitive AML cells•Desumoylation regulates specific transcriptional programs and participates in apoptosis•The ROS/SUMO axis is not induced in chemoresistant AML cells•Inhibition of the SUMO pathway with anacardic acid can overcome chemoresistance In this study, Bossis et al. show that treatment of acute myeloid leukemia cells with chemotherapeutic drugs induces a ROS-dependent loss of SUMO conjugation, which is involved in the activation of specific transcriptional programs and apoptosis. In addition, chemoresistance is associated with impaired activation of this ROS/SUMO axis. However, its targeting restores the death of chemoresistant AML cells and might thus be a way to overcome chemoresistance in patients