title: POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature.
abstract: The t(8;21)(q22;q22) translocation, present in approximately 5% of adult acute myeloid leukemia (AML) cases, produces the AML1/ETO (AE) fusion protein. Dysregulation of the Pit/Oct/Unc (POU) domain-containing transcription factor POU4F1 is a recurring abnormality in t(8;21) AML. In this study, we showed that POU4F1 overexpression is highly correlated with, but not caused by, AE. We observed that AE markedly increases the self-renewal capacity of myeloid progenitors from murine bone marrow or fetal liver and drives the expansion of these cells in liquid culture. POU4F1 is neither necessary nor sufficient for these AE-dependent properties, suggesting that it contributes to leukemia through novel mechanisms. To identify targets of POU4F1, we performed gene expression profiling in primary mouse cells with genetically defined levels of POU4F1 and identified 140 differentially expressed genes. This expression signature was significantly enriched in human t(8;21) AML samples and was sufficient to cluster t(8;21) AML samples in an unsupervised hierarchical analysis. Among the most highly differentially expressed genes, half are known AML1/ETO targets, implying that the unique transcriptional signature of t(8;21) AML is, in part, attributable to POU4F1 and not AML1/ETO itself. These genes provide novel candidates for understanding the biology and developing therapeutic approaches for t(8;21) AML.
authors.affiliation: Department of Internal Medicine, Division of Oncology, Stem Cell Biology Section, Washington University, St Louis, MO 63110, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Fortier
authors.forename: J E
authors.initials: JE
authors.lastname: Payton
authors.forename: P
authors.initials: P
authors.lastname: Cahan
authors.forename: T J
authors.initials: TJ
authors.lastname: Ley
authors.forename: M J
authors.initials: MJ
authors.lastname: Walter
authors.forename: T A
authors.initials: TA
authors.lastname: Graubert
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D005333:Fetus / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050819:Transcription Factor Brn-3A / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: C107844:AML1-ETO fusion protein, human; D014408:Biomarkers, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C494188:POU4F1 protein, human; C494189:Pou4f1 protein, mouse; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; D050819:Transcription Factor Brn-3A