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Normal Hemopoiesis

Dose-dependent repression of T-cell and natural killer cell genes by PU.1 enforces myeloid and B-cell identity

Leukemia volume 22, pages 1214–1225 (2008)Cite this article

Abstract

The Ets transcription factor PU.1, encoded by the gene Sfpi1, functions in a concentration-dependent manner to promote myeloid and B-cell development and has been implicated in myeloid and lymphoid leukemias. To determine the consequences of reducing PU.1 concentration during hematopoiesis, we analyzed mice with two distinct hypomorphic alleles of Sfpi1 that produce PU.1 at ∼20% (BN) or ∼2% (Blac) of wild-type levels. Myeloid development was impaired in these mice, but less severely than in Sfpi1 null mice. To identify the downstream target genes that respond to changes in PU.1 concentration, we analyzed ex vivo interleukin-3 dependent myeloid cell lines established from Sfpi1BN/BN, Sfpi1Blac/Blac and Sfpi1−/− fetal liver cells. Unexpectedly, many T-cell and natural killer cell genes were expressed in Sfpi1−/− cells and repressed in a dose-dependent manner in Sfpi1Blac/Blac and Sfpi1BN/BN cells. This pattern of dose-dependent T/NK-cell gene repression also occurred in ex vivo interleukin-7 dependent progenitor B cell lines. These results suggest that PU.1 functions in a concentration-dependent manner to repress T-cell and natural killer cell fates while promoting myeloid and B-cell fates.

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Acknowledgements

We thank the Affymetrix GeneChip Microarray Core (Cincinnati Children's Hospital Medical Center) for processing samples, Phil Sanford of the Gene Targeted Mouse Service (University of Cincinnati) for advice and H Leighton Grimes (Cincinnati Children's Hospital Medical Center) and Brock Schweitzer (University of Cincinnati) for helpful discussions. MBK is a PhD candidate at University of Cincinnati, and this work is submitted in partial fulfillment of the degree requirements. This work was supported by National Institutes of Health grant AI052175 and Ohio Cancer Research Associates grant 5407.

Contribution: MBK, IBH and RPD designed and performed experiments and collected data. AJJ and XZ performed experiments. MBK, SG and AGJ analyzed and interpreted data and performed statistical analyses. MBK and RPD drafted the manuscript.

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Authors and Affiliations

  1. Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    M B Kamath, I B Houston, A J Janovski, X Zhu & R P DeKoter

  2. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    S Gowrisankar & A G Jegga

  3. Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, USA

    S Gowrisankar

  4. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    A G Jegga

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  1. M B Kamath
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Correspondence to R P DeKoter.

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Kamath, M., Houston, I., Janovski, A. et al. Dose-dependent repression of T-cell and natural killer cell genes by PU.1 enforces myeloid and B-cell identity. Leukemia 22, 1214–1225 (2008). https://doi.org/10.1038/leu.2008.67

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