title: AML1/ETO proteins control POU4F1/BRN3A expression and function in t(8;21) acute myeloid leukemia.
abstract: A variety of genetic lesions, including chromosomal translocations, internal tandem duplications, and mutations, have been described in acute myeloid leukemia (AML). Expression profiling has shown that chromosomal translocations, in particular, are associated with distinctive patterns of gene expression. AML exhibiting the translocation t(8;21), which fuses the AML1 and ETO genes, has such a characteristic expression profile. One gene whose expression is highly correlated with the presence of the AML1/ETO fusion is POU4F1, which encodes the POU homeodomain transcription factor BRN3A. Here we show using specific siRNA in t(8;21) cells and overexpression studies in progenitor cells that AML1/ETO promotes expression of POU4F1/BRN3A. This effect requires DNA-binding function of AML1/ETO, and accordingly, AML1/ETO is bound to the POU4F1 locus in t(8;21) cells. Functionally, whereas overexpression of Brn3a in murine hematopoietic progenitor cells induces terminal myeloid differentiation, coexpression of AML1/ETO or AML1/ETO9a blocks this effect. Furthermore, Brn3a reduction by shRNA impairs AML1/ETO-induced immortalization of murine progenitors. In summary, we identify POU4F1/BRN3A as a novel potential upregulated AML1/ETO target gene whose dramatically high expression may cooperate with AML1/ETO in t(8;21) cells.
authors.affiliation: Cancer Research UK Medical Oncology Unit, Barts and the London School of Medicine and Dentistry, University of London, London, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Dunne
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Gascoyne
authors.forename: T Andrew
authors.initials: TA
authors.lastname: Lister
authors.forename: Hugh J M
authors.initials: HJ
authors.lastname: Brady
authors.forename: Olaf
authors.initials: O
authors.lastname: Heidenreich
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D005333:Fetus; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D000075142:RUNX1 Translocation Partner 1 Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050819:Transcription Factor Brn-3A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C494188:POU4F1 protein, human; C494189:Pou4f1 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; D050819:Transcription Factor Brn-3A; D008156:Luciferases
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