title: 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.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Li S
authors.initials: LS
authors.lastname: Xu
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Sokalski
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hotke
authors.forename: Darah A
authors.initials: DA
authors.lastname: Christie
authors.forename: Oren
authors.initials: O
authors.lastname: Zarnett
authors.forename: Jan
authors.initials: J
authors.lastname: Piskorz
authors.forename: Gobi
authors.initials: G
authors.lastname: Thillainadesan
authors.forename: Joseph
authors.initials: J
authors.lastname: Torchia
authors.forename: Rodney P
authors.initials: RP
authors.lastname: DeKoter
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation / Q000276:immunology*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011947:Receptors, Antigen, B-Cell; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C113939:B cell linker protein; C514177:Spi-B protein, mouse