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ResearchIn-Press PreviewHematologyOncology Open Access | 10.1172/JCI173770
1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
Find articles by Ondrisova, L. in: JCI | PubMed | Google Scholar
1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
Find articles by Zeni, P. in: JCI | PubMed | Google Scholar |
1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic
2Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
3Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
54th Department of Internal Medicine – Haematology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic
6Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
8Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
9Cancer Science Unit, University of Southampton, Southampton, United Kingdom
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Published October 22, 2024 - More info
BTK inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL) lasting for several months. It remains unclear whether non-genetic adaptation mechanisms exist, allowing CLL cells’ survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70 % of CLL cases, ibrutinib treatment in vivo increases Akt activity above pre-therapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of FoxO1 transcription factor, which induces expression of Rictor, an assembly protein for mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knock-out or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to BCR inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically, and its inhibition induces CLL cells’ apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T-cell factors (CD40L, IL-4, and IL-21).