NF-κB suppresses ROS levels in BCR–ABL+ cells to prevent activation of JNK and cell death

Elevated levels of reactive oxygen species are found in most oncogenically transformed cells and are proposed to promote cellular transformation through mechanisms such as inhibition of phosphatases. BCR-ABL, the oncoprotein associated with the majority of chronic myelogenous leukemias, induces accumulation of intracellular ROS causing enhanced signaling downstream of PI3K. Previously we have shown that the transcription factor NF-κB is activated by BCR-ABL expression and is required for BCR-ABL-mediated cellular transformation. Inhibition of IKKβ and NF-κB leads to cell death through an unknown mechanism. Here, we analyze the potential involvement of NF-κB in moderating BCR-ABL-induced ROS levels to protect from death in response to cell stress. The data confirm that BCR-ABL promotes ROS levels and demonstrate that NF-κB prevents excessive ROS levels. Inhibition of NF-κB leads to an increase in ROS levels and to cell death controlled through ROS-induced JNK activity. The data demonstrate that one function for NF-κB in oncogenesis is the suppression of oncoprotein-induced ROS levels and that inhibition of NF-κB in some cancers, including CML, will increase ROS levels and promote cell death