Cbfβ-SMMHC impairs differentiation of common lymphoid progenitors and reveals an essential role for RUNX in early B-cell development

The core-binding factor (CBF)associated leukemia fusion protein CBF beta-SMMHC impairs myeloid and lymphoid differentiation. By inhibiting RUNX function, the fusion oncoprotein predisposes specifically to acute myeloid leukemia in both patients and mouse models. We have shown that Cbf beta-SMMHC expression leads to a sustained reduction of circulating B lymphocytes in the mouse. In this study, we demonstrate that the activation of Cbf beta-SMMHC reduces pre-pro-B cells approximately 3-fold and pre-B cells more than 10-fold and that this differentiation block is cell-autonomous. The reduction of pre-pro-B cells coincided with an increase in apoptosis in this population. The number of common lymphoid progenitors (CLPs) were not affected; however, the expression of critical early B-cell factors Ebf1, Tcfe2a, and Pax5 was significantly reduced. In addition, Cbf beta-SMMHC reduced Rag1 and Rag2 expression and impaired V(D)J recombination in the CLPs. Furthermore, CLPs expressing Cbf beta-SMMHC also show inhibition of B cell-specific genes Cd79a, IgII1, VpreB1, and BIk. These results demonstrate that CBF/RUNX function is essential for the function of CLPs, the survival of pre-pro-B cells, and the establishment of a B lineage-specific transcriptional program. This study also provides a mechanistic basis for the myeloid-lineage bias of CBF beta-SMMHC-associated leukemia.