Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency

Mahadesh A J Prasad, Jonas Ungerbäck, Josefine Åhsberg, Rajesh Somasundaram, Tobias Strid, Malin Larsson, Robert Månsson, Ayla De Paepe, Henrik Lilljebjörn, Thoas Fioretos, James Hagman, Mikael Sigvardsson

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.