A model on the role of Ebf1 and Pax5 in B-cell differentiation that is based on the Prasad et al study is presented. The reciprocal effects of Ebf1 haploinsufficiency on DNA repair and survival genes are shown in combination with previously described effects on differentiation also supported by Pax5. Increased DNA damage in B-cell precursors normally leads to apoptosis; however, an increase in survival genes caused by Ebf1 haploinsufficiency supports survival. Subsequent selection of B-cell precursors with mutations in genes promoting leukemic transformation is augmented by the combined haploinsufficiency in Ebf1 and Pax5, possibly by accentuating a partial block at a highly proliferative stage of B-cell differentiation.