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Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1

Item Type:Article
Title:Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1
Creators Name:Rosenbauer, F. and Owens, B.M. and Yu, L. and Tumang, J.R. and Steidl, U. and Kutok, J.L. and Clayton, L.K. and Wagner, K. and Scheller, M. and Iwasaki, H. and Liu, C. and Hackanson, B. and Akashi, K. and Leutz, A. and Rothstein, T.L. and Plass, C. and Tenen, D.G.
Abstract:Tight regulation of transcription factors, such as PU.1, is crucial for generation of all hematopoietic lineages. We previously reported that mice with a deletion of an upstream regulatory element (URE) of the gene encoding PU.1 (Sfpi1) developed acute myeloid leukemia. Here we show that the URE has an essential role in orchestrating the dynamic PU.1 expression pattern required for lymphoid development and tumor suppression. URE deletion ablated B2 cells but stimulated growth of B1 cells in mice. The URE was a PU.1 enhancer in B cells but a repressor in T cell precursors. TCF transcription factors coordinated this repressor function and linked PU.1 to Wnt signaling. Failure of appropriate PU.1 repression in T cell progenitors with URE deletion disrupted differentiation and induced thymic transformation. Genome-wide DNA methylation assessment showed that epigenetic silencing of selective tumor suppressor genes completed PU.1-initiated transformation of lymphoid progenitors with URE deletion. These results elucidate how a single transcription factor, PU.1, through the cell context-specific activity of a key cis-regulatory element, affects the development of multiple cell lineages and can induce cancer.
Keywords:Thy-1 Antigens, B-Lymphocytes, Neoplastic Cell Transformation, DNA Methylation, Gene Expression Regulation, Lymphocytes, T-Cell Lymphoma, SCID Mice, Transgenic Mice, Promoter Regions, Proto-Oncogene Proteins, Nucleic Acid Regulatory Sequences, Signal Transduction, Stem Cells, TCF Transcription Factors, Thymus Gland, Trans-Activators, Wnt Proteins, beta Catenin, Animals, Mice
Source:Nature Genetics
ISSN:1061-4036
Publisher:Nature Publishing Group (U.S.A.)
Volume:38
Number:1
Page Range:27-37
Date:January 2006
Official Publication:https://doi.org/10.1038/ng1679
PubMed:View item in PubMed

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