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Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
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2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 125, no 26, 4052-4059 p.Article in journal (Refereed) Published
Abstract [en]

Early B-cell factor 1 (Ebf1) is a transcription factor with documented dose-dependent functions in normal and malignant B-lymphocyte development. To understand more about the roles of Ebf1 in malignant transformation, we investigated the impact of reduced functional Ebf1 dosage on mouse B-cell progenitors. Gene expression analysis suggested that Ebf1 was involved in the regulation of genes important for DNA repair and cell survival. Investigation of the DNA damage in steady state, as well as after induction of DNA damage by UV light, confirmed that pro-B cells lacking 1 functional allele of Ebf1 display signs of increased DNA damage. This correlated to reduced expression of DNA repair genes including Rad51, and chromatin immunoprecipitation data suggested that Rad51 is a direct target for Ebf1. Although reduced dosage of Ebf1 did not significantly increase tumor formation in mice, a dramatic increase in the frequency of pro-B cell leukemia was observed in mice with combined heterozygous mutations in the Ebf1 and Pax5 genes, revealing a synergistic effect of combined dose reduction of these proteins. Our data suggest that Ebf1 controls DNA repair in a dose-dependent manner providing a possible explanation to the frequent involvement of EBF1 gene loss in human leukemia.

Place, publisher, year, edition, pages
American Society of Hematology , 2015. Vol. 125, no 26, 4052-4059 p.
National Category
Clinical Medicine Biological Sciences
Identifiers
URN: urn:nbn:se:liu:diva-120281DOI: 10.1182/blood-2014-12-617282ISI: 000357284300016PubMedID: 25838350OAI: oai:DiVA.org:liu-120281DiVA: diva2:843023
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; Linkoping University; National Institutes of Health, National Institute of Allergy and Infectious Diseases [AI081878]

Available from: 2015-07-24 Created: 2015-07-24 Last updated: 2016-04-11

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Ungerbäck, JonasÅhsberg, JosefineSomasundaram, RajeshStrid, TobiasLarsson, MalinSigvardsson, Mikael
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