Abstract
The Wilms’ tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1GFP/+) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (<1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ETO+TEL/PDGFβR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit+lin−Sca-1+ (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1GFP/+ mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.
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Acknowledgements
We thank M Thomasson (Washington University) for MSCV-TEL/PDGFβR-ires-AML1/ETO, W Pear (University of Pennsylvania) for MSCV-p210BCR/ABL-ires-GFP, G Nolan (Stanford University) for Phoenix virus producer cell line, T Kitamura (Tokyo University, Japan) for Plat-E producer cell line, T Egawa (New York University) for technical advise, R Majeti for critical reading of this paper, L Jerabek for excellent laboratory management, C Muscat for antibody preparation; L Hidalgo, D Escoto and J Dollaga for animal care. We also appreciate E Passegue (University of California, San Francisco) and all the members of Weissman Lab for great discussion and technical help. The research was supported by the NIH (CA55209, CA86017 to ILW). NH was supported by the Japanese Society of Promotion of Science Fellowship, Yamada Memorial Foundation and Mitsubishi Pharma Research Foundation.
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Hosen, N., Shirakata, T., Nishida, S. et al. The Wilms’ tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis. Leukemia 21, 1783–1791 (2007). https://doi.org/10.1038/sj.leu.2404752
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DOI: https://doi.org/10.1038/sj.leu.2404752
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