Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development

S Malin, S McManus, C Cobaleda, M Novatchkova… - Nature …, 2010 - nature.com
S Malin, S McManus, C Cobaleda, M Novatchkova, A Delogu, P Bouillet, A Strasser
Nature immunology, 2010nature.com
Abstract 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 (VH) 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 …
Abstract
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 (VH) 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 VH gene recombination were normal in STAT5- or IL-7 receptor α-chain (IL-7Rα)-deficient pro-B cells rescued by Bcl-2. STAT5-expressing pro-B cells contained little or no active chromatin at most VH genes. In contrast, rearrangements of the immunoglobulin-κ light-chain locus (Igk) were more abundant in STAT5- or IL-7Rα-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.
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