Abstract
Transcription factors play important roles in lymphopoiesis. We have previously demonstrated that Bcl11a is essential for normal lymphocyte development in the mouse embryo. We report here that, in the adult mouse, Bcl11a is expressed in most hematopoietic cells and is highly enriched in B cells, early T cell progenitors, common lymphoid progenitors (CLPs), and hematopoietic stem cells (HSCs). In the adult mouse, Bcl11a deletion causes apoptosis in early B cells and CLPs and completely abolishes the lymphoid development potential of HSCs to B, T, and NK cells. Myeloid development, in contrast, is not obviously affected by the loss of Bcl11a. Bcl11a regulates expression of Bcl2, Bcl2-xL, and Mdm2, which inhibits p53 activities. Overexpression of Bcl2 and Mdm2, or p53 deficiency, rescues both lethality and proliferative defects in Bcl11a-deficient early B cells and enables the mutant CLPs to differentiate to lymphocytes. Bcl11a is therefore essential for lymphopoiesis and negatively regulates p53 activities. Deletion of Bcl11a may represent a new approach for generating a mouse model that completely lacks an adaptive immune system.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptive Immunity / genetics
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Adaptive Immunity / physiology
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Animals
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Apoptosis / drug effects
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Binding Sites / genetics
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Carrier Proteins / genetics
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Carrier Proteins / immunology*
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Carrier Proteins / metabolism*
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Cell Differentiation
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DNA-Binding Proteins
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Down-Regulation
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Gene Knockout Techniques
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Lymphopoiesis / genetics
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Lymphopoiesis / physiology*
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Mice, Transgenic
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology*
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Nuclear Proteins / metabolism*
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Precursor Cells, B-Lymphoid / cytology
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Precursor Cells, B-Lymphoid / drug effects
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Precursor Cells, B-Lymphoid / immunology
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Precursor Cells, B-Lymphoid / metabolism
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Precursor Cells, T-Lymphoid / cytology
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Precursor Cells, T-Lymphoid / immunology
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Precursor Cells, T-Lymphoid / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-bcl-2 / pharmacology
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Repressor Proteins
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Bcl11a protein, mouse
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Carrier Proteins
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DNA-Binding Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins c-bcl-2
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Repressor Proteins
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Tumor Suppressor Protein p53
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2