Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells.
Blood
; 144(2): 156-170, 2024 Jul 11.
Article
in En
| MEDLINE
| ID: mdl-38684032
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hematopoietic Stem Cells
/
Cyclin-Dependent Kinase 6
Limits:
Animals
/
Humans
Language:
En
Journal:
Blood
Year:
2024
Document type:
Article
Affiliation country:
Austria