Genetic and pharmacologic regulation of cyclin dependent kinase 4 and 6 activity in mammalian hematopoiesis Public Deposited

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  • March 20, 2019
Creator
  • Johnson, Søren Morgan
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Tight regulation of the cell cycle is required to allow necessary cellular proliferation while avoiding uncontrolled growth and cancer. In mammalian hematopoiesis, this regulation is particularly important because hematopoietic stem and progenitor cells (HSPC) must continuously and rapidly replenish circulating blood cells. Such rapid proliferation leaves HSPC particularly susceptible to damage from ionizing radiation (IR), and also increases the risk of hematologic malignancies. Cyclin dependent kinases (CDK) 4 and 6 are required for the G1/S-phase transition in HSPC, whereas most other tissues do not depend on CDK4/6 activity for cellular proliferation. Because of this tissue-specific requirement for CDK4/6 in the hematopoietic system we sought to identify the cell cycle effects of selective CDK4/6 inhibitors in cell lines. Highly potent and selective CDK4/6 inhibitors arrested CDK4/6-dependent cells in the G1 phase of the cell cycle, while not affecting cells which proliferate independently of CDK4/6. This selective cell cycle arrest successfully protected arrested cells from IR, whereas less selective CDK inhibitors did not, and cells that did not require CDK4/6 for proliferation were also not protected from IR. In mice, inhibition of CDK4/6 slowed the proliferation of HSPC, thereby increasing murine survival after IR exposure. Furthermore, therapeutic IR delivered to mice with autochthonous melanomas remained an effective anti-tumor treatment when the mice received transient CDK4/6 inhibition, though CDK4/6 inhibition did improve survival from the IR. Such pharmacologic manipulation of CDK4/6 activity would be of use after radiological accidents or as an adjuvant to clinical radiotherapy.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology."
Advisor
  • Sharpless, Norman
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  • Chapel Hill, NC
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  • Open access
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