Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia
Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia
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DOI：
10.1182/blood-2005-06-2219
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发表时间：
2006-02-15
期刊：
影响因子：
20.3
通讯作者：
Taub, JW
中科院分区：
文献类型：
--
作者：
Ge, YB;Dombkowski, AA;Taub, JW
患有唐氏综合征（DS）的急性巨核细胞白血病（AMkL）儿童与非DS AMkL患者相比具有非常高的生存率。在基本上所有DS AMkL病例中，在X连锁转录因子基因GATA 1中鉴定的体细胞突变导致合成具有改变的反式激活活性的较短（40 kDa）蛋白（GATA 1），并可能导致GATA 1靶基因表达改变。使用Affytelium U133 A微阵列芯片，我们确定了551个差异表达的基因之间的DS和非DS AMkL样品。非DS组的骨髓基质细胞抗原2（BST 2）基因（编码一种可能参与白血病细胞和骨髓基质细胞之间相互作用的跨膜糖蛋白）转录本比DS组高7.3倍（通过实时聚合酶链反应验证）。其他研究证实了GATA 1蛋白结合和BST 2启动子的反式激活;然而，与全长GATA 1相比，GATA 1对BST 2启动子活性的刺激大幅降低。CMK亚系，转染BST 2 cDNA和HS-5骨髓基质细胞孵育，表现出高达1.7倍减少阿糖胞苷（ara-C）诱导的细胞凋亡，与模拟转染细胞相比。我们的研究结果表明，占IDS和非DS AMkL的情况下，生存差异的基因可以通过微阵列分析和差异基因表达可能反映相对的反式激活能力的GATA 1和全长GATA 1蛋白。
Children with Down syndrome (DS) with acute megakaryocytic leukemia (AMkL) have very high survival rates compared with non-DS AMkL patients. Somatic mutations identified in the X-linked transcription factor gene, GATA1, in essentially all DS AMkL cases result in the synthesis of a shorter (40 kDa) protein (GATA1s) with altered transactivation activity and may lead to altered expression of GATA1 target genes. Using the Affymetrix U133A microarray chip, we identified 551 differentially expressed genes between DS and non-DS AMkL samples. Transcripts for the bone marrow stromal-cell antigen 2 (BST2) gene, encoding a transmembrane glycoprotein potentially involved in interactions between leukemia cells and bone marrow stromal cells, were 7.3-fold higher (validated by real-time polymerase chain reaction) in the non-DS compared with the DS group. Additional studies confirmed GATA1 protein binding and transactivation of the BST2 promoter; however, stimulation of BST2 promoter activity by GATA1s was substantially reduced compared with the full-length GATA1. CMK sublines, transfected with the BST2 cDNA and incubated with HS-5 bone marrow stromal cells, exhibited up to 1.7-fold reduced cytosine arabinoside (ara-C)-induced apoptosis, compared with mock-transfected cells. Our results demonstrate that genes that account for differences in survival between IDS and non-DS AMkL cases may be identified by microarray analysis and that differential geneexpression may reflect relative trans-activation capacities of the GATA1s and full-length GATA1 proteins.