دورية أكاديمية
Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells.
العنوان: | Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells. |
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المؤلفون: | Mayer IM; University of Veterinary Medicine, Vienna, Vienna, Austria., Doma E; University of Veterinary Medicine, Vienna, Vienna, Austria., Klampfl T; University of Veterinary Medicine, Vienna, Vienna, Austria., Prchal-Murphy M; University of Veterinary Medicine, Vienna, Vienna, Austria., Kollmann S; University of Veterinary Medicine, Vienna, Vienna, Austria., Schirripa A; University of Veterinary Medicine, Vienna, Vienna, Austria., Scheiblecker L; University of Veterinary Medicine, Vienna, Vienna, Austria., Zojer M; University of Veterinary Medicine, Vienna, Vienna, Austria., Kunowska N; Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Graz, Austria., Gebrail L; University of Veterinary Medicine, Vienna, Vienna, Austria., Shaw LE; Department of Dermatology, Medical University of Vienna, Vienna, Austria., Mann U; Department of Dermatology, Medical University of Vienna, Vienna, Austria., Farr A; Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria., Grausenburger R; University of Veterinary Medicine, Vienna, Vienna, Austria., Heller G; Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria., Zebedin-Brandl E; Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria., Farlik M; Department of Dermatology, Medical University of Vienna, Vienna, Austria., Malumbres M; Cancer Cell Cycle Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Cell Division and Cancer Group, Spanish National Cancer Research Center, Madrid, Spain.; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain., Sexl V; University of Veterinary Medicine, Vienna, Vienna, Austria.; University of Innsbruck, Innsbruck, Austria., Kollmann K; University of Veterinary Medicine, Vienna, Vienna, Austria. |
المصدر: | Blood [Blood] 2024 Jul 11; Vol. 144 (2), pp. 156-170. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
مواضيع طبية MeSH: | Cyclin-Dependent Kinase 6*/metabolism , Cyclin-Dependent Kinase 6*/genetics , Hematopoietic Stem Cells*/metabolism , Hematopoietic Stem Cells*/cytology, 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 |
مستخلص: | 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.) |
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المشرفين على المادة: | EC 2.7.11.22 (Cyclin-Dependent Kinase 6) EC 2.7.11.22 (Cdk6 protein, mouse) EC 2.7.11.22 (CDK6 protein, human) |
تواريخ الأحداث: | Date Created: 20240429 Date Completed: 20240711 Latest Revision: 20240808 |
رمز التحديث: | 20240808 |
مُعرف محوري في PubMed: | PMC11302456 |
DOI: | 10.1182/blood.2023021985 |
PMID: | 38684032 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1528-0020 |
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DOI: | 10.1182/blood.2023021985 |