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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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HEMATOPOIESIS
B-cell development fails in the absence of the Pbx1 proto-oncogene
Mrinmoy Sanyal1,
James W. Tung2,
Holger Karsunky1,
Hong Zeng1,
Licia Selleri3,
Irving L. Weissman1,
Leonore A. Herzenberg2, and
Michael L. Cleary1
1 Department of Pathology and
2 Department of Genetics, Stanford University School of Medicine, Stanford, CA;
3 Department of Cell and Developmental Biology, Cornell University Medical School, New York, NY
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 CLPs 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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