Title (eng)

Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells

Author

Isabella M. Mayer   University of Veterinary Medicine Vienna

Karoline Kollmann   University of Veterinary Medicine Vienna

Veronika Sexl   University of Veterinary Medicine Vienna / Universität Innsbruck

Marcos Malumbres   Vall d'Hebron Institute of Oncology / Spanish National Cancer Research Centre / Institució Catalana de Recerca i Estudis Avançats

Matthias Farlik   Medical University of Vienna

Eva Zebedin-Brandl   Medical University of Vienna

Gerwin Heller   Medical University of Vienna

Reinhard Grausenburger   University of Veterinary Medicine Vienna

Alex Farr   Medical University of Vienna

Ulrike Mann   Medical University of Vienna

Lisa E. Shaw   Medical University of Vienna

Lea Gebrail   University of Veterinary Medicine Vienna

Natalia Kunowska   University of Graz

Markus Zojer   University of Veterinary Medicine Vienna

Lisa Scheiblecker   University of Veterinary Medicine Vienna

Alessia Schirripa   University of Veterinary Medicine Vienna

Eszter Doma   University of Veterinary Medicine Vienna

Thorsten Klampfl   University of Veterinary Medicine Vienna

Michaela Prchal-Murphy   University of Veterinary Medicine Vienna

Sebastian Kollmann   University of Veterinary Medicine Vienna

Publishing

American Society of Hematology

Description (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.

Object languages

English

Date

2024

Rights

This work is licensed under a
CC BY-NC-ND 4.0 - Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.

CC BY-NC-ND 4.0 International

http://creativecommons.org/licenses/by-nc-nd/4.0/

Classification

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

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