Repository logo
 

JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation.


Type

Article

Change log

Authors

Ahn, JS 
Li, J 
Chen, E 
Kent, DG 
Park, HJ 

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.

Description

Keywords

Apoptosis, Cell Line, Tumor, DNA Damage, Female, Forkhead Box Protein O3, Gene Expression Regulation, Neoplastic, Hematopoietic Stem Cells, Humans, Janus Kinase 2, Male, Mutation, Myeloproliferative Disorders, Neoplasms, Phosphatidylinositol 3-Kinases, Reactive Oxygen Species, Sodium-Hydrogen Exchangers, bcl-X Protein

Journal Title

Oncogene

Conference Name

Journal ISSN

0950-9232
1476-5594

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (097922/Z/11/B)
Cancer Research Uk (None)
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.