The Mixed Lineage Leukemia (MLL) Fusion-Associated Gene AF4 Promotes CD133 Transcription
The Mixed Lineage Leukemia (MLL) Fusion-Associated Gene AF4 Promotes CD133 Transcription
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DOI：
10.1158/0008-5472.can-11-3589
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发表时间：
2012-04-15
期刊：
影响因子：
11.2
通讯作者：
Moffat, Jason
中科院分区：
文献类型：
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作者：
Mak, Anthony B.;Nixon, Allison M. L.;Moffat, Jason
AC 133表位已被用作来自多种组织谱系的正常干细胞和癌症干细胞的标记物。为了鉴定调节CD 133表达的转录因子，我们在内源性表达CD 133的Caco-2癌细胞和从异源启动子表达CD 133的工程化HEK 293细胞中进行了平行的大规模RNA干扰筛选。在两种筛选之间的比较分析之后鉴定了转录因子AF 4。然后，我们表明，AF 4是在多种癌细胞系中的CD 133转录的启动子。AF 4的敲低导致CD 133转录水平的显著降低。重要的是，儿童急性淋巴细胞白血病（ALL）的一个亚群含有融合癌基因，该融合癌基因是由染色体易位引起的，该易位将混合谱系白血病（MLL）基因和AF 4基因并列。对CD 133在MLL-AF 4依赖性ALL细胞中的功能作用的研究表明，CD 133是白血病细胞生存所需的。总之，我们的研究结果表明，AF 4依赖性调节CD 133表达，这是ALL细胞生长所必需的。因此，CD 133可能代表癌症亚组中的治疗靶点。Cancer Res; 72（8）; 1929-34. (C)2012年AACR。
The AC133 epitope has been used as a marker for both normal and cancer stem cells from multiple tissue lineages. To identify transcription factors that regulate CD133 expression, we conducted parallel large-scale RNA interference screens in Caco-2 cancer cells that endogenously express CD133 and in engineered HEK293 cells that express CD133 from a heterologous promoter. The transcription factor AF4 was identified following a comparative analysis between the two screens. We then showed that AF4 is a promoter of CD133 transcription in multiple cancer cell lines. Knockdown of AF4 resulted in a dramatic reduction in CD133 transcript levels. Importantly, a subset of pediatric acute lymphoblastic leukemias (ALL) harbor a fusion oncogene results from a chromosomal translocation that juxtaposes the mixed-lineage leukemia (MLL) gene and the AF4 gene. An investigation of the functional role of CD133 in the MLL-AF4-dependent ALL cells revealed that CD133 was required for leukemia cell survival. Together, our findings show AF4-dependent regulation of CD133 expression, which is required for the growth of ALL cells. CD133 may therefore represent a therapeutic target in a subset of cancers. Cancer Res; 72(8); 1929-34. (C) 2012 AACR.