| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2000: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
The transcription factors Bach1 and Bach2, members of the BTB-basic region leucine zipper (bZip) factor family, bind to a 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive element and the related Maf-recognition element (MARE) by forming homodimers or heterodirners with Maf-related transcription factors. Among human hematopoietic cell lines (12 myeloid cell lines and 16 lymphocytic cell lines), BACH2 is expressed abundantly only in some B-lymphocytic cell lines. Enforced expression of BACH2 in a human Burkitt cell line, RAJI that does not express endogenous BACH2, resulted in marked reduction of clonogenic activity, indicating that BACH2 possesses an inhibitory effect on cell proliferation. A large-scale comparison of the expression profiles between a human B cell line without endogenous BACH2 expression and a BACH2-overexpressing subline, using two-color fluorescence hybridization of cDNA microarray, led to the identification of Bcl-2 homologue A1 with anti-apoptotic activity and
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EBI3 which is a homologue to IL-12 (p40) as target genes of Bach2. A1 and EBI3 were expressed in all human B-cell lines which do not express BACH2. However, no expression was detected in B-cell lines expressing BACH2. Luciferase reporter and gel retardation assays revealed the responsive elements in the 5' region of the human A1 gene. Hence Bach2 might be involved in repression of A1 gene at earlier stages of B-cell differentiation and control of B-cell apoptosis.
By fluorescent in situ hybridization, the BACH2 gene was localized to chromosome 6q15. Because deletion of the long arm of chromosome 6 (6q) is one of the commonest chromosomal alterations in human B-cell lymphoma, we examined for the loss of heterozygosity (LOH) of the BACH2 gene in human B-cell non-Hodgkin's lymphomas (NHL). Among 25 informative cases, 5 (20 %) showed LOH. To analyze the mutations of BACH2 gene in these lymphomas, we examine the structure of the BACH2 gene and determined the sequences of the all coding exons and the exon-intron boundaries. By direct sequence analysis, no mutations were detected in the f lymphoma samples with the LOH of BACH2 gene. These results indicate that BACH2 plays important roles irregulation of B cell proliferation, although it remains still elusive whether loss of BACH2 function is involved in B-cell tumorigenesis Less
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