Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1.
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.
Rosenbauer
Frank
F
Harvard Institutes of Medicine and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA. f.rosenbauer@mdc-berlin.de
Owens
Bronwyn M
BM
Yu
Li
L
Tumang
Joseph R
JR
Steidl
Ulrich
U
Kutok
Jeffery L
JL
Clayton
Linda K
LK
Wagner
Katharina
K
Scheller
Marina
M
Iwasaki
Hiromi
H
Liu
Chunhui
C
Hackanson
Björn
B
Akashi
Koichi
K
Leutz
Achim
A
Rothstein
Thomas L
TL
Plass
Christoph
C
Tenen
Daniel G
DG
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019175:DNA Methylation; D005786:Gene Expression Regulation; D008214:Lymphocytes / Q000473:pathology / Q000502:physiology*; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000254:growth & development / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D011518:Proto-Oncogene Proteins; D051820:TCF Transcription Factors; D018800:Thy-1 Antigens; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D000099232:Proto-Oncogene Protein Spi-1