Journal
GENE
Volume 851, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.gene.2022.147049
Keywords
RUNX1; AML1; Enhancer; Hematopoietic stem cell; Leukemia stem cell
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The generation of a tamoxifen-inducible CreERT2 transgenic mouse using a stem cell enhancer provides a powerful tool for labeling and studying normal and malignant hematopoietic stem cells at all developmental stages.
A cis-regulatory genetic element which targets gene expression to stem cells, termed stem cell enhancer, serves as a molecular handle for stem cell-specific genetic engineering. Here we show the generation and characterization of a tamoxifen-inducible CreERT2 transgenic (Tg) mouse employing previously identified hematopoietic stem cell (HSC) enhancer for Runx1, eR1 (+24 m). Kinetic analysis of labeled cells after tamoxifen injection and transplantation assays revealed that eR1-driven CreERT2 activity marks dormant adult HSCs which slowly but steadily contribute to unperturbed hematopoiesis. Fetal and child HSCs that are uniformly or intermediately active were also efficiently targeted. Notably, a gene ablation at distinct developmental stages, enabled by this system, resulted in different phenotypes. Similarly, an oncogenic Kras induction at distinct ages caused different spectrums of malignant diseases. These results demonstrate that the eR1-CreERT2 Tg mouse serves as a powerful resource for the analyses of both normal and malignant HSCs at all developmental stages.
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