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

Frank Rosenbauer, Bronwyn M. Owens, Li Yu, Joseph R. Tumang, Ulrich G. Steidl, Jeffery L. Kutok, Linda K. Clayton, Katharina Wagner, Marina Scheller, Hiromi Iwasaki, Chunhui Liu, Björn Hackanson, Koichi Akashi, Achim Leutz, Thomas L. Rothstein, Christoph Plass, Daniel G. Tenen

Research output: Contribution to journalArticle

151 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)27-37
Number of pages11
JournalNature Genetics
Volume38
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

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Regulator Genes
Lymphocytes
Transcription Factors
Growth
T-Lymphoid Precursor Cells
TCF Transcription Factors
Cell Lineage
DNA Methylation
Tumor Suppressor Genes
Acute Myeloid Leukemia
Epigenomics
Neoplasms
B-Lymphocytes
Genome
T-Lymphocytes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. / Rosenbauer, Frank; Owens, Bronwyn M.; Yu, Li; Tumang, Joseph R.; Steidl, Ulrich G.; Kutok, Jeffery L.; Clayton, Linda K.; Wagner, Katharina; Scheller, Marina; Iwasaki, Hiromi; Liu, Chunhui; Hackanson, Björn; Akashi, Koichi; Leutz, Achim; Rothstein, Thomas L.; Plass, Christoph; Tenen, Daniel G.

In: Nature Genetics, Vol. 38, No. 1, 01.2006, p. 27-37.

Research output: Contribution to journalArticle

Rosenbauer, F, Owens, BM, Yu, L, Tumang, JR, Steidl, UG, Kutok, JL, Clayton, LK, Wagner, K, Scheller, M, Iwasaki, H, Liu, C, Hackanson, B, Akashi, K, Leutz, A, Rothstein, TL, Plass, C & Tenen, DG 2006, 'Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1', Nature Genetics, vol. 38, no. 1, pp. 27-37. https://doi.org/10.1038/ng1679
Rosenbauer, Frank ; Owens, Bronwyn M. ; Yu, Li ; Tumang, Joseph R. ; Steidl, Ulrich G. ; Kutok, Jeffery L. ; Clayton, Linda K. ; Wagner, Katharina ; Scheller, Marina ; Iwasaki, Hiromi ; Liu, Chunhui ; Hackanson, Björn ; Akashi, Koichi ; Leutz, Achim ; Rothstein, Thomas L. ; Plass, Christoph ; Tenen, Daniel G. / Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. In: Nature Genetics. 2006 ; Vol. 38, No. 1. pp. 27-37.
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