Compound haploinsufficiencies of Ebf1 and Runx1 genes impede B cell lineage progression

Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated the synergistic activation of Cd79a (mb-1) genes by EBF1 and its functional partner, RUNX1. Here, we identified consequences of Ebf1 haploinsufficiency together with haploinsufficiency of Runx1 genes in mice. Although numbers of "committed" pro-B cells were maintained in Ebf1 +/- Runx1 +/- (ER het ) mice, activation of B cell-specific gene transcription was depressed in these cells. Expression of genes encoding Aiolos, κ0 sterile transcripts, CD2 and CD25 were reduced and delayed in ER het pro-B cells, whereas surface expression of BP-1 was increased on late pro-B cells in ER het mice. Late pre-B and immature and mature B cells were decreased in the bone marrow of Ebf1 +/- (E het ) mice and were nearly absent in ER het mice. Although we did not observe significant effects of haploinsuficiencies on IgH or Igκ rearrangements, a relative lack of Igλ rearrangements was detected in E het and ER het pre-B cells. Together, these observations suggest that B cell lineage progression is impaired at multiple stages in the bone marrow of E het and ER het mice. Furthermore, enforced expression of EBF1 and RUNX1 in terminally differentiated plasmacytoma cells activated multiple early B cell-specific genes synergistically. Collectively, these studies illuminate the effects of reduced Ebf1 dosage and the compounding effects of reduced Runx1 dosage. Our data confirm and extend the importance of EBF1 in regulating target genes and Ig gene rearrangements necessary for B cell lineage specification, developmental progression, and homeostasis.