Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia.


Type
Article
Change log
Authors
Ecker, Veronika 
Stumpf, Martina 
Brandmeier, Lisa 
Neumayer, Tanja 
Pfeuffer, Lisa 
Abstract

Current therapeutic approaches for chronic lymphocytic leukemia (CLL) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the phosphatidylinositol-3-phosphate/AKT (PI3K/AKT)-signaling pathway may be leveraged to trigger CLL cell death. Though counterintuitive, our data show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SH2-containing-inositol-5'-phosphatase-1 (SHIP1) induces acute cell death in CLL cells. Our mechanistic studies reveal that increased AKT activity upon inhibition of SHIP1 leads to increased mitochondrial respiration and causes excessive accumulation of reactive oxygen species (ROS), resulting in cell death in CLL with immunogenic features. Our results demonstrate that CLL cells critically depend on mechanisms to fine-tune PI3K/AKT activity, allowing sustained proliferation and survival but avoid ROS-induced cell death and suggest transient SHIP1-inhibition as an unexpectedly promising concept for CLL therapy.

Description
Keywords
Cell Line, Tumor, Mitochondria, Animals, Mice, Transgenic, Humans, Mice, Disease Progression, Reactive Oxygen Species, RNA, Small Interfering, Transplantation, Homologous, Immunohistochemistry, Xenograft Model Antitumor Assays, Signal Transduction, Cell Death, Cell Survival, Oxidative Phosphorylation, Proto-Oncogene Proteins c-akt, Leukemia, Lymphocytic, Chronic, B-Cell, Phosphatidylinositol 3-Kinases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, RNA-Seq
Journal Title
Nature communications
Conference Name
Journal ISSN
2041-1723
Volume Title
12
Publisher