phaidra.vetmeduni.ac.at o:3470 DOI 10.1182/blood.2023021985 Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells 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. eng 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 2024-09-03T08:03:45.161Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Mayer;Isabella M.; FN:Isabella M. Mayer X-ORCID:https://orcid.org/0000-0002-9164-9547 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kollmann;Karoline; FN:Karoline Kollmann X-ORCID:https://orcid.org/0000-0002-7937-4245 END:VCARD BEGIN:VCARD VERSION:3.0 N:Sexl;Veronika; FN:Veronika Sexl X-ORCID:https://orcid.org/0000-0001-9363-0412 END:VCARD BEGIN:VCARD VERSION:3.0 N:Malumbres;Marcos; FN:Marcos Malumbres END:VCARD BEGIN:VCARD VERSION:3.0 N:Farlik;Matthias; FN:Matthias Farlik X-ORCID:https://orcid.org/0000-0003-0698-2992 END:VCARD BEGIN:VCARD VERSION:3.0 N:Zebedin-Brandl;Eva; FN:Eva Zebedin-Brandl END:VCARD BEGIN:VCARD VERSION:3.0 N:Heller;Gerwin; FN:Gerwin Heller END:VCARD BEGIN:VCARD VERSION:3.0 N:Grausenburger;Reinhard; FN:Reinhard Grausenburger X-ORCID:https://orcid.org/0000-0002-5972-3372 END:VCARD BEGIN:VCARD VERSION:3.0 N:Farr;Alex; FN:Alex Farr X-ORCID:https://orcid.org/0000-0002-4628-9052 END:VCARD BEGIN:VCARD VERSION:3.0 N:Mann;Ulrike; FN:Ulrike Mann END:VCARD BEGIN:VCARD VERSION:3.0 N:Shaw;Lisa E.; FN:Lisa E. Shaw X-ORCID:https://orcid.org/0000-0003-2273-7655 END:VCARD BEGIN:VCARD VERSION:3.0 N:Gebrail;Lea; FN:Lea Gebrail END:VCARD BEGIN:VCARD VERSION:3.0 N:Kunowska;Natalia; FN:Natalia Kunowska END:VCARD BEGIN:VCARD VERSION:3.0 N:Zojer;Markus; FN:Markus Zojer END:VCARD BEGIN:VCARD VERSION:3.0 N:Scheiblecker;Lisa; FN:Lisa Scheiblecker END:VCARD BEGIN:VCARD VERSION:3.0 N:Schirripa;Alessia; FN:Alessia Schirripa X-ORCID:https://orcid.org/0000-0001-5446-9136 END:VCARD BEGIN:VCARD VERSION:3.0 N:Doma;Eszter; FN:Eszter Doma X-ORCID:https://orcid.org/0000-0003-2989-1022 END:VCARD BEGIN:VCARD VERSION:3.0 N:Klampfl;Thorsten; FN:Thorsten Klampfl X-ORCID:https://orcid.org/0000-0002-6666-9773 END:VCARD BEGIN:VCARD VERSION:3.0 N:Prchal-Murphy;Michaela; FN:Michaela Prchal-Murphy END:VCARD BEGIN:VCARD VERSION:3.0 N:Kollmann;Sebastian; FN:Sebastian Kollmann X-ORCID:https://orcid.org/0000-0001-7911-9896 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by-nc-nd/4.0 application/pdf 5803023 https://phaidra.vetmeduni.ac.at/o:3470 https://phaidra.vetmeduni.ac.at/api/object/o:3470/thumbnail LOMv1.0 discipline