B-cell development fails in the absence of the Pbx1 proto-oncogene.
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.
Sanyal
Mrinmoy
M
Department of Pathology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
Tung
James W
JW
Karsunky
Holger
H
Zeng
Hong
H
Selleri
Licia
L
Weissman
Irving L
IL
Herzenberg
Leonore A
LA
Cleary
Michael L
ML
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D001755:Blastocyst / Q000276:immunology; D002678:Chimera / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D016654:Genes, RAG-1; D006412:Hematopoietic Stem Cells / Q000166:cytology; D018398:Homeodomain Proteins / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000196:embryology; D038041:Lymphopoiesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D014157:Transcription Factors / Q000235:genetics*
D018398:Homeodomain Proteins; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D014157:Transcription Factors