Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development.
STAT5 and interleukin 7 (IL-7) signaling are thought to control B lymphopoiesis by regulating the expression of key transcription factors and by activating variable (V(H)) gene segments at the immunoglobulin heavy-chain (Igh) locus. Using conditional mutagenesis to delete the gene encoding the transcription factor STAT5, we demonstrate that the development of pro-B cells was restored by transgenic expression of the prosurvival protein Bcl-2, which compensated for loss of the antiapoptotic protein Mcl-1. Expression of the genes encoding the B cell-specification factor EBF1 and the B cell-commitment protein Pax5 as well as V(H) gene recombination were normal in STAT5- or IL-7 receptor alpha-chain (IL-7Ralpha)-deficient pro-B cells rescued by Bcl-2. STAT5-expressing pro-B cells contained little or no active chromatin at most V(H) genes. In contrast, rearrangements of the immunoglobulin-kappa light-chain locus (Igk) were more abundant in STAT5- or IL-7Ralpha-deficient pro-B cells. Hence, STAT5 and IL-7 signaling control cell survival and the developmental ordering of immunoglobulin gene rearrangements by suppressing premature Igk recombination in pro-B cells.
Malin
Stephen
S
Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
McManus
Shane
S
Cobaleda
César
C
Novatchkova
Maria
M
Delogu
Alessio
A
Bouillet
Philippe
P
Strasser
Andreas
A
Busslinger
Meinrad
M
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D015321:Gene Rearrangement / Q000235:genetics / Q000276:immunology; D005803:Genes, Immunoglobulin / Q000235:genetics / Q000276:immunology; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology; D054503:Lymphoid Progenitor Cells / Q000166:cytology* / Q000276:immunology; D038041:Lymphopoiesis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor