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

Bonadies, N; Neururer, Ch; Steege, A; Vallabhapurapu, S; Pabst, T; Mueller, B U (2010). PU.1 is regulated by NF-kappaB through a novel binding site in a 17 kb upstream enhancer element. Oncogene, 29(7), pp. 1062-72. Basingstoke, UK: Nature Publishing Group 10.1038/onc.2009.371

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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-kappaB (NF-kappaB) to activate PU.1 expression through a novel site within the URE. We found sequence variations of this particular NF-kappaB site in 4 of 120 AML patients. These variant NF-kappaB 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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of General Internal Medicine (DAIM) > Clinic of General Internal Medicine > Centre of Competence for General Internal Medicine 04 Faculty of Medicine > Department of General Internal Medicine (DAIM) > Clinic of General Internal Medicine 04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
UniBE Contributor:	Bonadies, Nicolas, Neururer, Christine, Steege, Andreas, Vallabhapurapu, Subrahmanya, Pabst, Thomas Niklaus, Müller, Beatrice Ursula
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:08
Last Modified:	02 Mar 2023 23:20
Publisher DOI:	10.1038/onc.2009.371
PubMed ID:	19966852
Web of Science ID:	000274604400012
URI:	https://boris.unibe.ch/id/eprint/319 (FactScience: 197571)