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Acute Leukemias

POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature

Leukemia volume 24, pages 950–957 (2010)Cite this article

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Abstract

The t(8;21)(q22;q22) translocation, present in ∼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.

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Acknowledgements

This study was supported by funding from the NIH (P01 CA101937) and Gabrielle's Angel Foundation. Cell sorting and gene expression profiling were performed in Siteman Cancer Center core facilities that are supported by the NCI (P30 CA91842). We thank Eric Turner and Michael Tomasson for providing critical reagents (plasmids and mutant mice) and Mieke Hoock for expert mouse colony management.

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  1. Department of Internal Medicine, Division of Oncology, Stem Cell Biology Section, Washington University, St Louis, MO, USA

    J M Fortier, P Cahan, T J Ley, M J Walter & T A Graubert

  2. Department of Genetics, Division of Oncology, Stem Cell Biology Section, Washington University, St Louis, MO, USA

    J M Fortier, P Cahan, T J Ley & M J Walter

  3. Department of Pathology and Immunology, Washington University, St Louis, MO, USA

    J E Payton

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  1. J M Fortier
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Fortier, J., Payton, J., Cahan, P. et al. POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature. Leukemia 24, 950–957 (2010). https://doi.org/10.1038/leu.2010.61

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