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Blood. 2015 Jan 1;125(1):90-101. doi: 10.1182/blood-2014-06-584417. Epub 2014 Oct 23.

CDK6 as a key regulator of hematopoietic and leukemic stem cell activation.

Author information

1
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
2
Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria;
3
Cell Division and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain; and.
4
Research Institute of Molecular Pathology, Vienna, Austria.

Abstract

The cyclin-dependent kinase 6 (CDK6) and CDK4 have redundant functions in regulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (hematopoietic stem cells [HSCs] and leukemic stem cells [LSCs]) that exceeds its function as a cell-cycle regulator. Although hematopoiesis appears normal under steady-state conditions, Cdk6(-/-) HSCs do not efficiently repopulate upon competitive transplantation, and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil treatment. We find that activation of HSCs requires CDK6, which interferes with the transcription of key regulators, including Egr1. Transcriptional profiling of HSCs is consistent with the central role of Egr1. The impaired repopulation capacity extends to BCR-ABL(p210+) LSCs. Transplantation with BCR-ABL(p210+)-infected bone marrow from Cdk6(-/-) mice fails to induce disease, although recipient mice do harbor LSCs. Egr1 knock-down in Cdk6(-/-) BCR-ABL(p210+) LSKs significantly enhances the potential to form colonies, underlining the importance of the CDK6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.

PMID:
25342715
PMCID:
PMC4281832
DOI:
10.1182/blood-2014-06-584417
[Indexed for MEDLINE]
Free PMC Article

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