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Blood, 1 August 2008, Vol. 112, No. 3, pp. 551-559.
Prepublished online as a Blood First Edition Paper on May 27, 2008; DOI 10.1182/blood-2007-11-125930.
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HEMATOPOIESIS AND STEM CELLS
Lack of nuclear factor- B2/p100 causes a RelB-dependent block in early B lymphopoiesis
Feng Guo1,
Simone Tänzer1,
Meinrad Busslinger2, and
Falk Weih1,3
1 Research Group Immunology, Leibniz-Institute for Age Research—Fritz-Lipmann-Institute, Jena, Germany;
2 Research Institute of Molecular Pathology, Vienna, Austria; and
3 Friedrich-Schiller-University, Jena, Germany
Nuclear factor- B (NF-B) transcription factors regulate B-cell development and survival. However, whether they also have a role during early steps of B-cell differentiation is largely unclear. Here, we show that constitutive activation of the alternative NF-B pathway in p100–/– knockin mice resulted in a block of early B-cell development at the transition from the pre–pro-B to the pro–B-cell stage due to enhanced RelB activity. Expression of the essential B-cell transcription factors EBF and in particular Pax5 was reduced in p100–/– B-cell precursors in a RelB-dependent manner, resulting in reduced mRNA levels of B lineage-specific genes. Moreover, enhanced RelB function in p100–/– B-cell precursors was accompanied by increased expression of B lineage–inappropriate genes, such as C/EBP , correlating with a markedly increased myeloid differentiation potential of p100–/– progenitor B cells. Ectopic expression of Pax5 in hematopoietic progenitors restored early B-cell development in p100–/– bone marrow, suggesting that impaired early B lymphopoiesis in mice lacking the p100 inhibitor may be due to down-regulation of Pax5 expression. Thus, tightly controlled p100 processing and RelB activation is essential for normal B lymphopoiesis and lymphoid/myeloid lineage decision in bone marrow.
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