Haematologica (Jun 2018)
BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells
- Mark Wroblewski,
- Marina Scheller-Wendorff,
- Florian Udonta,
- Raimund Bauer,
- Jara Schlichting,
- Lin Zhao,
- Isabel Ben Batalla,
- Victoria Gensch,
- Sarina Päsler,
- Lei Wu,
- Marek Wanior,
- Hanna Taipaleenmäki,
- Simona Bolamperti,
- Zeynab Najafova,
- Klaus Pantel,
- Carsten Bokemeyer,
- Jun Qi,
- Eric Hesse,
- Stefan Knapp,
- Steven Johnsen,
- Sonja Loges
Affiliations
- Mark Wroblewski
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Marina Scheller-Wendorff
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Germany
- Florian Udonta
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Raimund Bauer
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Jara Schlichting
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Lin Zhao
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Isabel Ben Batalla
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Victoria Gensch
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Sarina Päsler
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Lei Wu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA;Department of Medicine, Harvard Medical School, Boston, MA, USA
- Marek Wanior
- Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University and Buchmann Institute for Molecular Life Sciences, Frankfurt am Main, Germany
- Hanna Taipaleenmäki
- Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand & Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Simona Bolamperti
- Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand & Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Zeynab Najafova
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany
- Klaus Pantel
- Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Carsten Bokemeyer
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Jun Qi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA;Department of Medicine, Harvard Medical School, Boston, MA, USA
- Eric Hesse
- Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand & Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Stefan Knapp
- Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University and Buchmann Institute for Molecular Life Sciences, Frankfurt am Main, Germany;Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford, Old Road Campus Research Building, UK;German Cancer Consortium (DKTK) Frankfurt am Main, Germany
- Steven Johnsen
- Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany
- Sonja Loges
- Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- DOI
- https://doi.org/10.3324/haematol.2017.181354
- Journal volume & issue
-
Vol. 103,
no. 6
Abstract
Although inhibitors of bromodomain and extra terminal domain (BET) proteins show promising clinical activity in different hematologic malignancies, a systematic analysis of the consequences of pharmacological BET inhibition on healthy hematopoietic (stem) cells is urgently needed. We found that JQ1 treatment decreases the numbers of pre-, immature and mature B cells while numbers of early pro-B cells remain constant. In addition, JQ1 treatment increases apoptosis in T cells, all together leading to reduced cellularity in thymus, bone marrow and spleen. Furthermore, JQ1 induces proliferation of long-term hematopoietic stem cells, thereby increasing stem cell numbers. Due to increased numbers, JQ1-treated hematopoietic stem cells engrafted better after stem cell transplantation and repopulated the hematopoietic system significantly faster after sublethal myeloablation. As quantity and functionality of hematopoietic stem cells determine the duration of life-threatening myelosuppression, BET inhibition might benefit patients in myelosuppressive conditions.
