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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-04-1288. This Article Full Text (PDF) All Versions of this Article: 2002-04-1288v1 101/1/270    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Vangala, R. K Articles by Behre, G. Search for Related Content PubMed PubMed Citation Articles by Vangala, R. K Articles by Behre, G. Social Bookmarking                   What's this? Submitted April 30, 2002 Accepted July 30, 2002 The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia Rajani K Vangala, Marion S Heiss-Neumann, Janki S Rangatia, Sheo M Singh, Claudia Schoch, Daniel G Tenen, Wolfgang Hiddemann, and Gerhard Behre* Department of Medicine III, Ludwig Maxmimilian University, Munich, Germany Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA * Corresponding author; email: gerdbehre{at}aol.com. 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)-positive Kasumi-1 cells. AML1-ETO binds to the ß3ß4-region in the DNA binding domain of PU.1 and displaces the co-activator c-Jun from PU.1, thus downregulating PU.1's transcriptional activity. This physical interaction of AML1-ETO and PU.1 did not abolish the DNA binding capacity of PU.1. AML1-ETO downregulates the transactivation capacity of PU.1 in myeloid U937 cells, and the expression levels of PU.1 target genes in AML 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 anti-proliferative function of PU.1. Overexpression of PU.1, however, differentiates AML1-ETO expressing Kasumi-1 cells to the monocytic lineage. Thus, PU.1's function is downregulated by AML1-ETO in t(8;21) myeloid leukemia, whereas overexpression of PU.1 restores normal differentiation. 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