期刊
JOURNAL OF IMMUNOLOGY
卷 189, 期 7, 页码 3347-3354出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1201267
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资金
- Canadian Institutes of Health Research [MOP-106581]
- National Sciences and Engineering Research Council [386046]
B cell acute lymphoblastic leukemia (B-ALL) is frequently associated with mutations or chromosomal translocations of genes encoding transcription factors. Conditional deletion of genes encoding the E26-transformation-specific transcription factors, PU.1 and Spi-B, in B cells (DPB mice) leads to B-ALL in mice at 100% incidence rate and with a median survival of 21 wk. We hypothesized that PU.1 and Spi-B may redundantly activate transcription of genes encoding tumor suppressors in the B cell lineage. Characterization of aging DPB mice showed that leukemia cells expressing IL-7R were found in enlarged thymuses. IL-7R-expressing B-ALL cells grew in culture in response to IL-7 and could be maintained as cell lines. Cultured DPB cells expressed reduced levels of B cell linker protein (BLNK), a known tumor suppressor gene, compared with controls. The Blnk promoter contained a predicted PU. 1 and/or Spi-B binding site that was required for promoter activity and occupied by PU. 1 and/or Spi-B as determined by chromatin immunoprecipitation. Restoration of BLNK expression in cultured DPB cells opposed IL-7-dependent proliferation and induced early apoptosis. We conclude that the tumor suppressor BLNK is a target of transcriptional activation by PU. 1 and Spi-B in the B cell lineage. The Journal of Immunology, 2012, 189: 3347-3354.
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