title: JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation.
abstract: 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 the 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 with 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 with stem cells. Inactivation of FOXO proteins and elevation of intracellular ROS are characteristics common to many cancers, and hence these findings are likely to be of relevance beyond the MPN field.
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: E
authors.initials: E
authors.lastname: Chen
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: D G
authors.initials: DG
authors.lastname: Kent
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: H J
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.|Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Green
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D017382:Reactive Oxygen Species; D017923:Sodium-Hydrogen Exchangers; D051020:bcl-X Protein; C069139:growth factor-activatable Na-H exchanger NHE-1; D019869:Phosphatidylinositol 3-Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2