1. Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells.
- Author
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Mayer IM, Doma E, Klampfl T, Prchal-Murphy M, Kollmann S, Schirripa A, Scheiblecker L, Zojer M, Kunowska N, Gebrail L, Shaw LE, Mann U, Farr A, Grausenburger R, Heller G, Zebedin-Brandl E, Farlik M, Malumbres M, Sexl V, and Kollmann K
- Subjects
- Animals, Mice, Humans, Adult Stem Cells metabolism, Adult Stem Cells cytology, Cell Proliferation, Cell Differentiation, Mice, Inbred C57BL, Hematopoietic Stem Cell Transplantation, Cell Self Renewal drug effects, Cyclin-Dependent Kinase 6 metabolism, Cyclin-Dependent Kinase 6 genetics, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells cytology
- Abstract
Abstract: 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., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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