title: The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia.
abstract: The transcription factor PU.1 plays a pivotal role in normal myeloid differentiation. PU.1(-/-) mice exhibit a complete block in myeloid differentiation. Heterozygous PU.1 mutations were reported in some patients with acute myeloid leukemia (AML), but not in AML with translocation t(8;21), which gives rise to the fusion gene AML1-ETO. Here we report a negative functional impact of AML1-ETO on the transcriptional activity of PU.1. AML1-ETO physically binds to PU.1 in t(8;21)(+) Kasumi-1 cells. AML1-ETO binds to the beta(3)beta(4) region in the DNA-binding domain of PU.1 and displaces the coactivator c-Jun from PU.1, thus down-regulating the transcriptional activity of PU.1. This physical interaction of AML1-ETO and PU.1 did not abolish the DNA-binding capacity of PU.1. AML1-ETO down-regulates the transactivation capacity of PU.1 in myeloid U937 cells, and the expression levels of PU.1 target genes in AML French-American-British (FAB) subtype M2 patients with t(8;21) were lower than in patients without t(8;21). Conditional expression of AML1-ETO causes proliferation in mouse bone marrow cells and inhibits antiproliferative function of PU.1. Overexpression of PU.1, however, differentiates AML1-ETO-expressing Kasumi-1 cells to the monocytic lineage. Thus, the function of PU.1 is down-regulated by AML1-ETO in t(8;21) myeloid leukemia, whereas overexpression of PU.1 restores normal differentiation.
authors.affiliation: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University Munich and GSF-National Research Center for Environment and Health, Germany.
authors.forename: Rajani K
authors.initials: RK
authors.lastname: Vangala
authors.forename: Marion S
authors.initials: MS
authors.lastname: Heiss-Neumann
authors.forename: Janki S
authors.initials: JS
authors.lastname: Rangatia
authors.forename: Sheo M
authors.initials: SM
authors.lastname: Singh
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Behre
mesh_terms: D000818:Animals; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002455:Cell Division; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun; D000075142:RUNX1 Translocation Partner 1 Protein; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D000075142:RUNX1 Translocation Partner 1 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C107844:AML1-ETO fusion protein, human