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

Veronika Ecker, Martina Stumpf, Lisa Brandmeier, Tanja Neumayer, Lisa Pfeuffer, Thomas Engleitner, Ingo Ringshausen, Nina Nelson, Manfred Jücker, Stefan Wanninger, Thorsten Zenz, Clemens Wendtner, Katrin Manske, Katja Steiger, Roland Rad, Markus Müschen, Jürgen Ruland and Maike Buchner ()
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Veronika Ecker: Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich
Martina Stumpf: Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich
Lisa Brandmeier: Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich
Tanja Neumayer: Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich
Lisa Pfeuffer: Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich
Thomas Engleitner: TranslaTUM - Central Institute for Translational Cancer Research, Technical University of Munich
Ingo Ringshausen: Wellcome/MRC Cambridge Stem Cell Institute and Department of Haematology, Jeffrey Cheah Biomedical Centre, University of Cambridge
Nina Nelson: Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf
Manfred Jücker: Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf
Stefan Wanninger: Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich
Thorsten Zenz: University Hospital and University of Zurich
Clemens Wendtner: Munich Clinic Schwabing, Academic Teaching Hospital, Ludwig-Maximilians University (LMU)
Katrin Manske: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München
Katja Steiger: Institute of Pathology, Technische Universität München
Roland Rad: TranslaTUM - Central Institute for Translational Cancer Research, Technical University of Munich
Markus Müschen: Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine
Jürgen Ruland: Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich
Maike Buchner: Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23752-2

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