Regulation of B cell linker protein transcription by PU.1 and Spi-B in murine B cell acute lymphoblastic leukemia.

Abstract

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 (ΔPB 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 ΔPB 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 ΔPB 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 ΔPB 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.

• Authors: Li S Xu, Kristen M Sokalski, Kathryn Hotke, Darah A Christie, Oren Zarnett, Jan Piskorz, Gobi Thillainadesan, Joseph Torchia, Rodney P DeKoter
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 189 Issue 7 Pg. 3347-54 (Oct 01 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22956576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• B cell linker protein
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-ets
• Receptors, Antigen, B-Cell
• Spi-B protein, mouse
• Trans-Activators
• proto-oncogene protein Spi-1

Topics

• Adaptor Proteins, Signal Transducing (genetics, immunology, metabolism)
• Animals
• B-Lymphocytes (immunology, metabolism, pathology)
• Cell Line, Tumor
• Cell Lineage (genetics, immunology)
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• NIH 3T3 Cells
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (genetics, immunology, metabolism)
• Promoter Regions, Genetic (immunology)
• Protein Binding (genetics, immunology)
• Proto-Oncogene Proteins (physiology)
• Proto-Oncogene Proteins c-ets (physiology)
• Receptors, Antigen, B-Cell (physiology)
• Trans-Activators (physiology)
• Transcriptional Activation (immunology)