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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4191-4199.
Prepublished online as a Blood First Edition Paper on January 23, 2007; DOI 10.1182/blood-2006-10-054213.
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Submitted October 25, 2006
Accepted January 15, 2007
B cell development fails in the absence of the Pbx1 proto-oncogene
Mrinmoy Sanyal, James W Tung, Holger Karsunky, Hong Zeng, Licia Selleri, Irving L Weissman, Leonore A Herzenberg, and Michael L Cleary*
Department of Pathology, Stanford University School of Medicine, Stanford, CA
Department of Cell and Developmental Biology, Cornell University Medical School, New York, NY
Department of Genetics, Stanford University School of Medicine, Stanford, CA
* Corresponding author; email: michael.cleary{at}stanford.edu.
Pbx1, a homeodomain transcription factor that was originally identified as the product of a proto-oncogene in acute pre-B cell leukemia, is a global regulator of embryonic development. However, embryonic lethality in its absence has prevented an assessment of its role in B cell development. Here, using Rag1-deficient blastocyst complementation assays, we demonstrate that Pbx1 null embryonic stem (ES) cells fail to generate common lymphoid progenitors (CLPs) resulting in a complete lack of B and NK cells, and a partial impairment of T cell development in chimeric mice. A critical role for Pbx1 was confirmed by rescue of B cell development from CLP following restoration of its expression in Pbx1-deficient ES cells. In adoptive transfer experiments, B cell development from Pbx1-deficient fetal liver cells was also severely compromised, but not erased, since transient B lymphopoiesis was detected in Rag-deficient recipients. Conditional inactivation of Pbx1 in pro-B (CD19+) cells and thereafter, revealed that Pbx1 is not necessary for B cell development to proceed from the pro-B cell stage. Thus, Pbx1 critically functions at a stage between hematopoietic stem cell development and B cell commitment, and therefore is one of the earliest-acting transcription factors that regulate de novo B lineage lymphopoiesis.
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