1. Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia
- Author
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Ecker, Veronika, Stumpf, Martina, Brandmeier, Lisa, Neumayer, Tanja, Pfeuffer, Lisa, Engleitner, Thomas, Ringshausen, Ingo, Nelson, Nina, Jücker, Manfred, Wanninger, Stefan, Zenz, Thorsten, Wendtner, Clemens, Manske, Katrin, Steiger, Katja, Rad, Roland, Müschen, Markus, Ruland, Jürgen, Buchner, Maike, Ringshausen, Ingo [0000-0002-7247-311X], Zenz, Thorsten [0000-0001-7890-9845], Steiger, Katja [0000-0002-7269-5433], Rad, Roland [0000-0002-6849-9659], Müschen, Markus [0000-0002-6064-8613], Ruland, Jürgen [0000-0002-8381-3597], Buchner, Maike [0000-0002-4196-096X], Apollo - University of Cambridge Repository, University of Zurich, and Buchner, Maike
- Subjects
Chronic lymphocytic leukaemia ,Cancer therapy ,Cell Survival ,Science ,610 Medicine & health ,1600 General Chemistry ,Mice, Transgenic ,13 ,Oxidative Phosphorylation ,38 ,13/1 ,Mice ,Phosphatidylinositol 3-Kinases ,1300 General Biochemistry, Genetics and Molecular Biology ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,Animals ,Humans ,Transplantation, Homologous ,RNA-Seq ,RNA, Small Interfering ,13/89 ,neoplasms ,692/4028/67/1059 ,64 ,Cell Death ,article ,64/110 ,Immunohistochemistry ,Leukemia, Lymphocytic, Chronic, B-Cell ,Xenograft Model Antitumor Assays ,3100 General Physics and Astronomy ,Mitochondria ,13/31 ,631/67/1990/283/1895 ,Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases ,10032 Clinic for Oncology and Hematology ,13/51 ,13/95 ,Disease Progression ,Reactive Oxygen Species ,Proto-Oncogene Proteins c-akt ,Signal Transduction - 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., Current therapeutic approaches in chronic lymphocytic leukemia (CLL) focus on the suppression of PI3K/AKT signaling. Here, the authors show that CLL cells are vulnerable to hyperactivation of the PI3K/AKT signaling pathway and suggest this as a promising concept for CLL therapy.
- Published
- 2021