https://phaidra.vetmeduni.ac.at/o:3470 Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells Mayer, Isabella M. Isabella M. Mayer 0000-0002-9164-9547 University of Veterinary Medicine Vienna Kollmann, Karoline Karoline Kollmann 0000-0002-7937-4245 University of Veterinary Medicine Vienna Sexl, Veronika Veronika Sexl 0000-0001-9363-0412 University of Veterinary Medicine Vienna / Universität Innsbruck Malumbres, Marcos Marcos Malumbres Vall d'Hebron Institute of Oncology / Spanish National Cancer Research Centre / Institució Catalana de Recerca i Estudis Avançats Farlik, Matthias Matthias Farlik 0000-0003-0698-2992 Medical University of Vienna Zebedin-Brandl, Eva Eva Zebedin-Brandl Medical University of Vienna Heller, Gerwin Gerwin Heller Medical University of Vienna Grausenburger, Reinhard Reinhard Grausenburger 0000-0002-5972-3372 University of Veterinary Medicine Vienna Farr, Alex Alex Farr 0000-0002-4628-9052 Medical University of Vienna Mann, Ulrike Ulrike Mann Medical University of Vienna Shaw, Lisa E. Lisa E. Shaw 0000-0003-2273-7655 Medical University of Vienna Gebrail, Lea Lea Gebrail University of Veterinary Medicine Vienna Kunowska, Natalia Natalia Kunowska University of Graz Zojer, Markus Markus Zojer University of Veterinary Medicine Vienna Scheiblecker, Lisa Lisa Scheiblecker University of Veterinary Medicine Vienna Schirripa, Alessia Alessia Schirripa 0000-0001-5446-9136 University of Veterinary Medicine Vienna Doma, Eszter Eszter Doma 0000-0003-2989-1022 University of Veterinary Medicine Vienna Klampfl, Thorsten Thorsten Klampfl 0000-0002-6666-9773 University of Veterinary Medicine Vienna Prchal-Murphy, Michaela Michaela Prchal-Murphy University of Veterinary Medicine Vienna Kollmann, Sebastian Sebastian Kollmann 0000-0001-7911-9896 University of Veterinary Medicine Vienna American Society of Hematology text eng Hematopoietic stem cells (HSCs) are characterized by the ability to self-renew and to replenish the hematopoietic system. The cell-cycle kinase cyclin-dependent kinase 6 (CDK6) regulates transcription, whereby it has both kinase-dependent and kinase-independent functions. Herein, we describe the complex role of CDK6, balancing quiescence, proliferation, self-renewal, and differentiation in activated HSCs. Mouse HSCs expressing kinase-inactivated CDK6 show enhanced long-term repopulation and homing, whereas HSCs lacking CDK6 have impaired functionality. The transcriptomes of basal and serially transplanted HSCs expressing kinase-inactivated CDK6 exhibit an expression pattern dominated by HSC quiescence and self-renewal, supporting a concept, in which myc-associated zinc finger protein (MAZ) and nuclear transcription factor Y subunit alpha (NFY-A) are critical CDK6 interactors. Pharmacologic kinase inhibition with a clinically used CDK4/6 inhibitor in murine and human HSCs validated our findings and resulted in increased repopulation capability and enhanced stemness. Our findings highlight a kinase-independent role of CDK6 in long-term HSC functionality. CDK6 kinase inhibition represents a possible strategy to improve HSC fitness. Cyclin-Dependent Kinase 6 Metabolism Genetics; Animals; Hematopoietic Stem Cells Metabolism Cytology; Mice; Humans; Adult Stem Cells Metabolism Cytology; Cell Proliferation; Cell Differentiation; Mice, Inbred C57BL; Hematopoietic Stem Cell Transplantation; Cell Self Renewal Drug effects http://creativecommons.org/licenses/by-nc-nd/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:3470/download 10.1182/blood.2023021985 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Blood 144(2), 156-170 (2024) Blood 144 2 156 170 5.53 MB 2024