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Hematopoiesis
BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells
Mark Wroblewski,1,2* Marina Scheller-Wendorff,1,2,3* Florian Udonta,1,2 Raimund Bauer,1,2 Jara Schlichting,1,2 Lin Zhao,1,2,4 Isabel Ben Batalla,1,2 Victoria Gensch,1,2 Sarina Päsler,1,2 Lei Wu,5,6 Marek Wanior,7 Hanna Taipaleenmäki,8 Simona Bolamperti,8 Zeynab Najafova,9 Klaus Pantel,2 Carsten Bokemeyer,1 Jun Qi,5,6 Eric Hesse,8 Stefan Knapp,7,10,11
Ferrata Storti Foundation
Steven Johnsen2,9 and Sonja Loges1,2
Haematologica 2018 Volume 103(6):939-948
1Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Germany; 4Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 5Department
of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; 6Department of Medicine, Harvard Medical School, Boston, MA, USA; 7Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University and Buchmann Institute for Molecular Life Sciences, Frankfurt am Main, Germany; 8Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand & Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 9Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany; 10Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford, Old Road Campus Research Building, UK and 11German Cancer Consortium (DKTK) Frankfurt am Main, Germany
*MWr and MS-W contributed equally to this work.
ABSTRACT
Although inhibitors of bromodomain and extra terminal domain (BET) proteins show promising clinical activity in different hema- tologic 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 bet- ter 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.
Introduction
The molecular mechanisms that govern hematopoietic stem cell (HSC) activity and lineage specification are increasingly well known and it has been demonstrated that abnormalities in pathways controlling these functions are a major cause of malignant transformation.1 Moreover, investigation of HSC biology has changed the view of cancer, and it is now believed that tumors are sustained by cells with a cancer stem cell phenotype, a highly malignant subpopulation which maintains the uncontrolled production of less malignant progeny.2 It is, therefore, essential to identify pathways that control key stem cell functions in order to better understand genes and mechanisms which are involved in transformation, tumor progression
Correspondence:
s.loges@uke.de
Received: October 12, 2017. Accepted: March 15, 2018. Pre-published: March 22, 2018.
doi:10.3324/haematol.2017.181354
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/939
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