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.) |
| References: | Science. 2022 Jan 14;375(6577):eabc1495. (PMID: 35025636) Cell. 2008 Dec 12;135(6):1118-29. (PMID: 19062086) Cancer Lett. 2017 Aug 28;402:142-152. (PMID: 28577976) EMBO J. 1998 Oct 1;17(19):5744-56. (PMID: 9755174) Cancer Cell. 2013 Aug 12;24(2):167-81. (PMID: 23948297) Oncogene. 1999 May 6;18(18):2818-27. (PMID: 10362252) Proc Natl Acad Sci U S A. 2021 Feb 16;118(7):. (PMID: 33558242) Science. 2016 Dec 2;354(6316):1156-1160. (PMID: 27738012) Cell Stem Cell. 2015 Mar 5;16(3):302-13. (PMID: 25704240) Cancer Discov. 2018 Jul;8(7):884-897. (PMID: 29899063) Cancers (Basel). 2022 Mar 28;14(7):. (PMID: 35406494) Blood Adv. 2021 Aug 10;5(15):3002-3015. (PMID: 34351390) Nature. 2020 Jul;583(7817):585-589. (PMID: 32669716) Blood Adv. 2021 Jan 12;5(1):39-53. (PMID: 33570624) Nature. 2018 Jan 24;553(7689):418-426. (PMID: 29364285) Blood. 2005 Sep 15;106(6):1901-10. (PMID: 15890683) Int J Cancer. 2020 Dec 1;147(11):2988-2995. (PMID: 32406095) Cell. 2008 Feb 22;132(4):631-44. (PMID: 18295580) Blood. 2019 Apr 11;133(15):1677-1690. (PMID: 30635286) Bone Marrow Transplant. 2021 Jun;56(6):1257-1265. (PMID: 33686251) Nature. 2014 Nov 20;515(7527):355-64. (PMID: 25409824) Cell Stem Cell. 2014 Oct 2;15(4):507-522. (PMID: 25158935) Blood. 2020 Sep 3;136(10):1144-1154. (PMID: 32438398) Nature. 2015 Feb 26;518(7540):542-6. (PMID: 25686605) Cell. 2004 Jul 23;118(2):149-61. (PMID: 15260986) Blood. 2015 Jan 1;125(1):90-101. (PMID: 25342715) Blood. 2011 Jun 9;117(23):6120-31. (PMID: 21508411) Cell Death Dis. 2011 May 26;2:e162. (PMID: 21614092) Front Immunol. 2021 Jun 24;12:650977. (PMID: 34248938) Cell. 2004 Aug 20;118(4):493-504. (PMID: 15315761) Nat Cell Biol. 2018 Jul;20(7):836-846. (PMID: 29915358) Blood. 2012 Feb 9;119(6):1380-9. (PMID: 22072554) PLoS Biol. 2004 Oct;2(10):e301. (PMID: 15459755) Curr Oncol. 2019 Jun;26(3):187-191. (PMID: 31285665) J Biol Chem. 2003 Sep 19;278(38):36966-72. (PMID: 12857729) Mol Cell Biol. 2018 Oct 29;38(22):. (PMID: 30181395) Nat Genet. 2022 Feb;54(2):202-212. (PMID: 35145304) Oncotarget. 2017 Jun 27;8(26):42343-42358. (PMID: 28418845) Mol Cell. 2014 Jan 23;53(2):193-208. (PMID: 24389100) Sci Transl Med. 2017 Apr 26;9(387):. (PMID: 28446688) |
| 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 |