Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency.
Författare
Summary, in English
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 as well as 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 one 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.
Avdelning/ar
- Molekylär lymfopoes
- Avdelningen för klinisk genetik
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
Publiceringsår
2015
Språk
Engelska
Sidor
4052-4059
Publikation/Tidskrift/Serie
Blood
Volym
125
Issue
26
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
American Society of Hematology
Ämne
- Hematology
Status
Published
Forskningsgrupp
- Molecular Lymphopoiesis
ISBN/ISSN/Övrigt
- ISSN: 1528-0020