Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1

Rosenbauer, Frank; Wagner, Katharina; Kutok, Jeffery L.; Iwasaki, Hiromi; Beau, Michelle M. Le; Okuno, Yutaka; Akashi, Koichi; Fiering, Steven; Tenen, Daniel G.

doi:10.1038/ng1361

Cited by 480 publications

(521 citation statements)

References 28 publications

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“…Most importantly, graded changes in each factor's concentration could result in committing a hematopoietic progenitor cell fate (Dahl and Simon, 2003;Rosenbauer et al, 2004). Our findings have supported general important roles of Ski in the hematopoietic cell system by inhibiting the function of critical transcription factors including PU.1 and GATA1.…”

Section: Discussionsupporting

confidence: 72%

“…PU.1-deficient mice lack mature myeloid cells. Aberrant expression of PU.1 (overexpression and graded reduction) significantly affects the hematopoietic lineage fate decisions and can promote erythroleukemia and myeloid leukemia in mice (Moreau-Gachelin et al, 1996;Rosenbauer et al, 2004;Metcalf et al, 2006). Given that Ski can strongly influence the biological role of PU.1, Ski might also be involved in the cell fate determination and leukemogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Ski can negatively regulates macrophage differentiation through its interaction with PU.1

2007

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

2007

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“…Overexpression and graded reduction of PU.1 induce erythroleukemia and myeloid leukemia in mice, respectively (Moreau-Gachelin et al, 1996;Rosenbauer et al, 2004). Furthermore, an aberrant expression of PU.1 is associated with the development of myeloid leukemia in humans (Muller et al, 2002;Vangala et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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The Ets transcription factor PU.1 is a hematopoietic master regulator essential for the development of myeloid and B-cell lineages. As we previously reported, PU.1 sometimes represses transcription on forming a complex with mSin3A-histone deacetyl transferase-MeCP2. Here, we show an interaction between PU.1 and DNA methyltransferases, DNA methyltransferase (Dnmt)3a and Dnmt3b (Dnmt3s). Glutathione-S-transferase pulldown assay revealed that PU.1 directly interacted with the ATRX domain of Dnmt3s through the ETS domain. Dnmt3s repressed the transcriptional activity of PU.1 on a reporter construct with trimerized PU.1-binding sites. The repression was recovered by addition of 5-aza-deoxycitidine, a DNA methyltransferase inhibitor, but not trichostatin A, a histone deacetylase inhibitor. Bisulfite sequence analysis revealed that several CpG sites in the promoter region neighboring the PU.1-binding sites were methylated when Dnmt3s were coexpressed with PU.1. We also showed that the CpG sites in the p16 INK4A promoter were methylated by overexpression of PU.1 in NIH3T3 cells, accompanied by a downregulation of p16 INK4A gene expression. These results suggest that PU.1 may downregulate its target genes through an epigenetic modification such as DNA methylation.

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“…Recently, it was shown that an 80% reduction of PU.1 expression is sufficient to cause acute myeloid leukaemia (AML) in mice (Rosenbauer et al, 2004). Our group has reported that heterozygous PU.1 mutations are observed in some AML patients (Mueller et al, 2002).…”

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confidence: 99%

Mutations of the transcription factor PU.1 are not associated with acute lymphoblastic leukaemia

et al. 2006

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The transcription factor PU.1 plays a crucial role during normal haematopoiesis in both myeloid cells and B-lymphocytes. Mice with a disruption in both alleles of the PU.1 locus were found to lack macrophages and B cells and had delayed appearance of neutrophils. In addition, critical decrease of PU.1 expression is sufficient to cause acute myeloid leukaemia (AML) and lymphomas in mice. Recently, we reported that heterozygous mutations in the PU.1 gene are present in some patients with AML. Thus, we hypothesised that PU.1 mutations might also contribute to the development of acute leukaemias of the B-cell lineage. Here, we screened 62 patients with B-cell acute lymphoblastic leukaemia (B-ALL) at diagnosis for genomic mutations by direct sequencing of all five exons of the PU.1 gene. We found no genomic alteration of the PU.1 gene suggesting that PU.1 mutations are not likely to be common in B-ALL.

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Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1

Cited by 480 publications

References 28 publications

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

Mutations of the transcription factor PU.1 are not associated with acute lymphoblastic leukaemia

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