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JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL
J S Ahn1,2, J Li1,2, E Chen1,2
1Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
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.
Insights
The JAK2V617F mutation in myeloproliferative neoplasms causes increased reactive oxygen species (ROS), inhibiting DNA damage response and promoting cell survival. This ROS accumulation is linked to aberrant PI3K signaling and reduced FOXO3A nuclear localization.
Area of Science:
- Molecular Biology
- Oncology
- Hematology
Background:
- The JAK2V617F mutation is prevalent in myeloproliferative neoplasms (MPNs), driving disease progression through dysregulated signaling.
- This mutation is linked to DNA damage accumulation and impaired apoptosis, contributing to uncontrolled cell proliferation.
- The precise mechanism by which JAK2V617F inhibits NHE-1 expression and affects cell survival pathways remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which JAK2V617F leads to impaired DNA damage response and cell survival.
- To investigate the role of reactive oxygen species (ROS) in the JAK2V617F-mediated inhibition of the NHE-1/Bcl-xL pathway.
- To explore the impact of JAK2V617F on FOXO3A localization and its implications in MPN pathogenesis.
Main Methods:
- Analysis of reactive oxygen species (ROS) levels in cells expressing JAK2V617F.
- Investigation of the PI3K signaling pathway and its effect on FOXO3A nuclear localization and catalase expression.
- Comparison of ROS levels and FOXO3A localization in patient-derived erythroblasts and hematopoietic stem cells (HSCs).
Main Results:
- JAK2V617F expression leads to increased ROS accumulation, which compromises the NHE-1/Bcl-xL deamidation pathway.
- Aberrant PI3K signaling in JAK2V617F-positive cells reduces FOXO3A nuclear localization and catalase expression, increasing ROS.
- Patient-derived MPN erythroblasts show higher ROS and lower nuclear FOXO3A compared to controls, while HSCs maintain FOXO3A nuclear localization.
Conclusions:
- Increased ROS due to aberrant PI3K signaling and reduced FOXO3A nuclear localization is a key mechanism by which JAK2V617F promotes cell survival in MPNs.
- FOXO3A localization and JAK2 signaling differ between hematopoietic stem cells and progenitors, suggesting context-dependent effects.
- The findings on FOXO inactivation and ROS elevation have potential implications for understanding and treating other cancers beyond MPNs.
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