title: Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency.
abstract: 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.
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, and.
authors.forename: Mahadesh A J
authors.initials: MA
authors.lastname: Prasad
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, and.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ungerbäck
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, and.
authors.forename: Josefine
authors.initials: J
authors.lastname: Åhsberg
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, and.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Somasundaram
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, and.
authors.forename: Tobias
authors.initials: T
authors.lastname: Strid
authors.affiliation: Bioinformatics Infrastructure for Life Sciences, IFM Bioinformatics, Linköping University, Linköping, Sweden;
authors.forename: Malin
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Center for Hematology and Regenerative Medicine Huddinge, Karolinska Institute, Stockholm, Sweden;
authors.forename: Robert
authors.initials: R
authors.lastname: Månsson
authors.affiliation: Bioinformatics Infrastructure for Life Sciences, IFM Bioinformatics, Linköping University, Linköping, Sweden;
authors.forename: Ayla
authors.initials: A
authors.lastname: De Paepe
authors.affiliation: Department of Clinical Genetics, Lund University, Lund, Sweden; and.
authors.forename: Henrik
authors.initials: H
authors.lastname: Lilljebjörn
authors.affiliation: Department of Clinical Genetics, Lund University, Lund, Sweden; and.
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO.
authors.forename: James
authors.initials: J
authors.lastname: Hagman
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, and.
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D020552:Comet Assay; D004249:DNA Damage / Q000235:genetics*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057895:Haploinsufficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051757:PAX5 Transcription Factor / Q000235:genetics*; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*
chemical_list: C489921:Ebf1 protein, mouse; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D015534:Trans-Activators
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