Study of the function and target genes of BACH transcripton factors.

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Transcription factor BACH1 and BACH2 bind to Maf recongnition elements by dimerizing with the small Maf transcription factors. The BACH1 mRNA was abundantly expressed in erythroid-megakaryocytic lineage cells. The MARE is known to act as a critical cis element of erythroid and megakaryocytic specific genes. The BACH1 gene is localized to chromosome 21q22.1, within the potential Down's syndrome-associated gene region. Actually, BACH1 was abundantly transcribed in cel lines derived from Down's syndrome-related megakaryocytic leukemia. To investigate the in vivo role of BACH1 overexpression in hematopoiesis, we generated BACH1 transgenic mice bearing the human BACH1 gene under the control of the regulatory element of the GATA-1 gene. Peripheral blood analysis in the transgenic mice revealed a significant reduced number of platelets without anemia. Histological analysis of bone marrow disclosed that the reticulin fibers were markedly increased. Megakaryocytes from the BACH1 transgenic mice … More exhibited significantly reduced proplatelet formation and maturation arrest. These results suggest that BACH1 plays important roles in transcriptional regulation of megakaryocyte-specific genes. Next, we also show here that BACH2 modifies the in vitro cytotoxicity of anticancer drugs in lymphoid leulemic cells. The inhibition of BCR/ABL tyrosine kinase activity by STI571 in Ph1 positive lymphoid leukemic cells results in induction of BACH2 expression. The cytotoxic effects of anticancer agents were studied by overexpression of BACH2 in Raji lymphoid cells. Clones overexpressing BACH2 were more sensitive to anticancer agents producing oxidative stress than control Raji cells. Interestingly, we found that these oxidative stressors induced the nuclear accumulation of BACH2. These results show that BACH2 promotes oxidative stress-induced cell death, suggest that combination chemotherapy involving STI571 and anticancer drugs that produce ROS may be of benefit in the treatment of Ph1-positive leukemia. Less