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

转录因子BACH1和BACH2通过与小的Maf转录因子二聚体结合到Maf识别元件上。BACH1 mRNA在红系巨核细胞中大量表达。MARE被认为是红系和巨核细胞特异性基因的关键顺式元件。BACH1基因定位于染色体21q22.1，位于潜在的唐氏综合征相关基因区域内。实际上，BACH1在来自唐氏综合征相关巨核细胞白血病的细胞系中大量转录。为了研究BACH1过表达在体内造血中的作用，我们在GATA-1基因调控元件的控制下，培养了携带人BACH1基因的BACH1转基因小鼠。转基因小鼠的外周血分析显示血小板数量显著减少，但无贫血。骨髓组织学分析显示网状蛋白纤维明显增加。来自BACH1转基因小鼠的巨核细胞…More显示出血小板形成明显减少和成熟阻滞。这些结果表明BACH1在巨核细胞特异性基因的转录调控中起重要作用。接下来，我们也在这里证明BACH2改变了抗癌药物在淋巴白血病细胞中的体外细胞毒性。在Ph1阳性淋巴白血病细胞中，STI571抑制BCR/ABL酪氨酸激酶活性可诱导BACH2表达。通过在Raji淋巴样细胞中过表达BACH2，研究了抗癌药物的细胞毒作用。过表达BACH2的克隆比对照Raji细胞对产生氧化应激的抗癌药物更敏感。有趣的是，我们发现这些氧化应激源诱导了BACH2的核积累。这些结果表明，BACH2促进氧化应激诱导的细胞死亡，提示涉及STI571和产生ROS的抗癌药物的联合化疗可能有益于治疗ph1阳性白血病。少

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