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Cbfb‐SMMHC impairs differentiation of Common Lymphoid Progenitors and reveals an essential role for RUNX in early B cell development
Author(s) -
Gerstein Rachel,
Kuo YaHuei,
Castilla Lucio
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.842.9
Subject(s) - recombination activating gene , b cell , biology , progenitor cell , microbiology and biotechnology , myeloid , cellular differentiation , pax5 , runx1 , population , stem cell , cancer research , immunology , haematopoiesis , antibody , gene , genetics , medicine , recombination , environmental health
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 both pre‐pro‐B and pro‐ B cells approximately 3 fold, 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 in CLPs were 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 and differentiation of pre‐pro‐B cells, and the establishment of a B lineage‐specific transcriptional program.