Casein kinase 1α essentially regulates thrombopoiesis by driving megakaryocyte maturation and cytoskeleton organization
Abstract
Abstract Throughout thrombopoiesis megakaryocytes (MKs) form proplatelets within the bone marrow (BM) and release platelets into BM sinusoids. Casein kinase 1α (CK1α) is a major player and thus, an important therapeutic target in several hematological malignancies. This study aimed to define the role of CK1α for the essential steps of thrombopoiesis and to dissect potential mechanisms of thrombocytopenia. MK-specific CK1α-deficiency resulted in a macrothrombocytopenia. Ck1αPf4Δ/Pf4Δ mice displayed a substantial BM hyperplasia with pivotal changes in MK nuclear lobulation and reduced contact to BM sinusoids. Ck1αPf4Δ/Pf4Δ MKs displayed a defective cytoskeleton organization reflected by a decreased amount of polymerized filamentous actin and disturbed microtubule dynamics due to p21/p53 accumulation and impaired Rho-associated protein kinase (ROCK)/LIM domain kinase (LIMK)/cofilin signaling. Further, pronounced defects in DMS (demarcation membrane system) polarization and proplatelet formation of Ck1αPf4Δ/Pf4Δ MKs, unraveled CK1α as a prerequisite for thrombopoiesis. Our findings could be translated into a human approach, because a CRISPR/Cas9–mediated genetic deletion of CSNK1A1 in MKs derived from human CD34+ progenitor cells resulted in a substantial defect in human MK maturation and platelet production. The present observations elucidated CK1α as an important signaling molecule in MK cytoskeletal dynamics and polarization, proplatelet formation, and polyploidization, thus highlighting the crucial role of CK1α in platelet biogenesis.
Article Details
Authors (25)
Ferdinand Kollotzek
Kristina Mott
3Institute of Experimental Biomedicine I, University Hospital of Würzburg, Würzburg, Germany
Melina Fischer
Betül Findik
4Department of Hematology, Oncology, Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
Vanessa Göb
3Institute of Experimental Biomedicine I, University Hospital of Würzburg, Würzburg, Germany
Mailin-Christin Manke
1DFG Heisenberg Group Cardiovascular Thrombo-Inflammation and Translational Thrombocardiology, University of Tübingen, Tübingen, Germany
Carla Emilia Borst
4Department of Hematology, Oncology, Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
Amin Polzin
University Hospital Düsseldorf, Düsseldorf, Germany
Martin D. Burkhalter
8Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
Anita Eckly
Tamam Bakchoul
Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tübingen, Germany
Melanie Philipp
Samuel J. Holzmayer
11German Cancer Consortium (DKTK partner site Tübingen), a partnership between the German Cancer Research Center and University Hospital Tübingen, Tübingen, Germany
Leticia Quintanilla-Fend
13Institute for Pathology, Department of General and Molecular Pathology, University Hospital Tübingen, Tübingen, Germany
Claudia Lengerke
Meinrad Gawaz
Catherine Leon
9University of Strasbourg, INSERM, Etablissement Français du Sang Grand-Est, Unité Mixte de Recherche (UMR S1255) Biologie et Pharmacologie des Plaquettes Sanguines, Translational Medicine Federation of Strasbourg, Strasbourg, France
David Stegner
2Julius Maximilian University of Würzburg, Rudolf Virchow Center for Integrative and Translational Bioimaging, Würzburg, Germany
Bernhard Nieswandt
9Institute of Experimental Biomedicine I, Würzburg, Germany
William Vainchenker
Markus Bender
3Institute of Experimental Biomedicine I, University Hospital of Würzburg, Würzburg, Germany
Julia Skokowa
Harald Schulze
3Institute of Experimental Biomedicine I, University Hospital of Würzburg, Würzburg, Germany
Patrick Münzer
1DFG Heisenberg Group Cardiovascular Thrombo-Inflammation and Translational Thrombocardiology, University of Tübingen, Tübingen, Germany
Oliver Borst