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PU.1 is regulated by NF-κB through a novel binding site in a 17 kb upstream enhancer element

Oncogene volume 29, pages 1062–1072 (2010)Cite this article

Abstract

The majority of patients with acute myeloid leukemia (AML) still die of their disease, and novel therapeutic concepts are needed. Timely expression of the hematopoietic master regulator PU.1 is crucial for normal development of myeloid and lymphoid cells. Targeted disruption of an upstream regulatory element (URE) located several kb upstream in the PU.1 promoter decreases PU.1 expression thereby inducing AML in mice. In addition, suppression of PU.1 has been observed in specific subtypes of human AML. Here, we identified nuclear factor-κB (NF-κB) to activate PU.1 expression through a novel site within the URE. We found sequence variations of this particular NF-κB site in 4 of 120 AML patients. These variant NF-κB sequences failed to mediate activation of PU.1. Moreover, the synergistic activation of PU.1 together with CEBPB through these variant sequences was also lost. Finally, AML patients with such variant sequences had suppressed PU.1 mRNA expression. This study suggests that changes of a single base pair in a distal element critically affect the regulation of the tumor suppressor gene PU.1 thereby contributing to the development of AML.

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Acknowledgements

This work was supported by a grant from the Swiss National Science Foundation SF 310000-113761 (to BUM), and a grant from the Swiss Cancer League, OCS 01731082005 (to BUM).

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Authors and Affiliations

  1. Department of Internal Medicine and Clinical Research, University Hospital Bern, University of Bern, Bern, Switzerland

    N Bonadies, Ch Neururer, A Steege, S Vallabhapurapu & B U Mueller

  2. Department of Medical Oncology, University Hospital Bern, University of Bern, Bern, Switzerland

    T Pabst

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  1. N Bonadies
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  2. Ch Neururer
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  3. A Steege
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  4. S Vallabhapurapu
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  5. T Pabst
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  6. B U Mueller
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Correspondence to B U Mueller.

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Bonadies, N., Neururer, C., Steege, A. et al. PU.1 is regulated by NF-κB through a novel binding site in a 17 kb upstream enhancer element. Oncogene 29, 1062–1072 (2010). https://doi.org/10.1038/onc.2009.371

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