Submitted July 31, 2007
Accepted October 10, 2007
Cbf
-SMMHC impairs differentiation of common lymphoid progenitors and reveals an essential role for RUNX in early B cell development
Ya-Huei Kuo, Rachel M Gerstein, and Lucio H Castilla*
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA, United States
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA, United States
* Corresponding author; email: lucio.castilla{at}umassmed.edu.
The core-binding factor (CBF)-associated leukemia fusion protein CBF
-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-SMMHC expression leads to a sustained reduction of circulating B lymphocytes in the mouse. In this study, we demonstrate that the activation of Cbf-SMMHC reduces pre-pro-B cells approximately 3 fold and pre-B cells over 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 were significantly reduced. In addition, Cbf-SMMHC reduced Rag1 and Rag2 expression, and impaired V(D)J recombination in the CLPs. Furthermore, CLPs expressing Cbf-SMMHC also show inhibition of B cell-specific genes Cd79a, Igll1, VpreB1 and Blk. 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-SMMHC-associated leukemia.
