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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1543-1551. Prepublished online as a Blood First Edition Paper on October 16, 2007; DOI 10.1182/blood-2007-07-104422. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-07-104422v1 111/3/1543    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kuo, Y.-H. Articles by Castilla, L. H. Search for Related Content PubMed PubMed Citation Articles by Kuo, Y.-H. Articles by Castilla, L. H. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Cbfβ-SMMHC impairs differentiation of common lymphoid progenitors and reveals an essential role for RUNX in early B-cell development Ya-Huei Kuo1, Rachel M. Gerstein2, and Lucio H. Castilla1 1 Program in Gene Function and Expression and 2 Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester The core-binding factor (CBF)–associated leukemia fusion protein CBFβ-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 Cbfβ-SMMHC expression leads to a sustained reduction of circulating B lymphocytes in the mouse. In this study, we demonstrate that the activation of Cbfβ-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, Cbfβ-SMMHC reduced Rag1 and Rag2 expression and impaired V(D)J recombination in the CLPs. Furthermore, CLPs expressing Cbfβ-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 CBFβ-SMMHC–associated leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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