Mayer, Isabella M. (University of Veterinary Medicine Vienna) Isabella M. Mayer Kollmann, Karoline (University of Veterinary Medicine Vienna) Karoline Kollmann Shaw, Lisa E. (Medical University of Vienna) Lisa E. Shaw Gebrail, Lea (University of Veterinary Medicine Vienna) Lea Gebrail Kunowska, Natalia (University of Graz) Natalia Kunowska Zojer, Markus (University of Veterinary Medicine Vienna) Markus Zojer Scheiblecker, Lisa (University of Veterinary Medicine Vienna) Lisa Scheiblecker Schirripa, Alessia (University of Veterinary Medicine Vienna) Alessia Schirripa Doma, Eszter (University of Veterinary Medicine Vienna) Eszter Doma Klampfl, Thorsten (University of Veterinary Medicine Vienna) Thorsten Klampfl Prchal-Murphy, Michaela (University of Veterinary Medicine Vienna) Michaela Prchal-Murphy Kollmann, Sebastian (University of Veterinary Medicine Vienna) Sebastian Kollmann Sexl, Veronika (University of Veterinary Medicine Vienna / Universität Innsbruck) Veronika Sexl Malumbres, Marcos (Vall d'Hebron Institute of Oncology / Spanish National Cancer Research Centre / Institució Catalana de Recerca i Estudis Avançats) Marcos Malumbres Farlik, Matthias (Medical University of Vienna) Matthias Farlik Zebedin-Brandl, Eva (Medical University of Vienna) Eva Zebedin-Brandl Heller, Gerwin (Medical University of Vienna) Gerwin Heller Grausenburger, Reinhard (University of Veterinary Medicine Vienna) Reinhard Grausenburger Farr, Alex (Medical University of Vienna) Alex Farr Mann, Ulrike (Medical University of Vienna) Ulrike Mann American Society of Hematology 2024 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. PDFDocument en 2024-09-03T07:54:17.981Z 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 5803023 b application/pdf CC BY-NC-ND 4.0 International