JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation
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Ahn, J. S., Li, J., Chen, E., Kent, D., Park, H. J., & Green, T. (2015). JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation. Oncogene https://doi.org/10.1038/onc.2015.285
The JAK2V617F mutation is found in most patients with a myeloproliferative neoplasm (MPN). This gain-of-function mutation dysregulates cytokine signaling and is associated with increased accumulation of DNA damage, a process likely to drive disease evolution. JAK2V617F inhibits NHE-1 upregulation in response to DNA damage and consequently represses Bcl-xL deamidation and apoptosis, thus giving rise to inappropriate cell survival. However, the mechanism whereby NHE-1 expression is inhibited by JAK2V617F is unknown. In this study we demonstrate that accumulation of reactive oxygen species (ROS) in cells expressing JAK2V617F compromises the NHE-1/Bcl-xL deamidation pathway by repressing NHE-1 upregulation in response to DNA damage. In JAK2V617F-positive cells, increased ROS levels results from aberrant PI3K signaling, which decreases nuclear localization of FOXO3A and decreases catalase expression. Furthermore, when compared to autologous control erythroblasts, clonally-derived JAK2V617F-positive erythroblasts from MPN patients displayed increased ROS levels and reduced nuclear FOXO3A. However, in hematopoietic stem cells (HSCs), FOXO3A is largely localized within the nuclei despite the presence of JAK2V617F mutation, suggesting that JAK2-FOXO signaling has a different effect on progenitors compared to stem cells. Inactivation of FOXO proteins and elevation of intracellular ROS are characteristics common to many cancers, and so these findings are likely to be of relevance beyond the MPN field.
JAK2V617F, apoptosis, FOXO3A, Bcl-xL, DNA damage
Work in the Green lab is supported by Leukemia and Lymphoma Research, Cancer Research UK, the Kay Kendall Leukaemia Fund, the NIHR Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre, and the Leukemia & Lymphoma Society of America. DGK was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (Ottawa, ON), and a Lady Tata Memorial Trust International Award for Research in Leukaemia (London, UK). HJP was supported by a postdoctoral fellowship from the Human Frontier Science Program.
External DOI: https://doi.org/10.1038/onc.2015.285
This record's URL: https://www.repository.cam.ac.uk/handle/1810/249284