Donnelley Centre and Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada.
Cancer Res. 2012 Apr 15;72(8):1929-34. doi: 10.1158/0008-5472.CAN-11-3589. Epub 2012 Feb 14.
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.
AC133 表位已被用作多个组织谱系的正常和癌症干细胞的标志物。为了鉴定调节 CD133 表达的转录因子，我们在天然表达 CD133 的 Caco-2 癌细胞和表达来自异源启动子的 CD133 的工程化 HEK293 细胞中进行了平行的大规模 RNA 干扰筛选。在对两个筛选进行比较分析后，鉴定出转录因子 AF4。然后我们表明，AF4 是多种癌细胞系中 CD133 转录的启动子。AF4 的敲低导致 CD133 转录本水平的显著降低。重要的是，一部分小儿急性淋巴细胞白血病 (ALL) 具有融合癌基因，这是由于染色体易位导致混合谱系白血病 (MLL) 基因和 AF4 基因并列。对 MLL-AF4 依赖性 ALL 细胞中 CD133 的功能作用的研究表明，CD133 是白血病细胞存活所必需的。总之，我们的研究结果表明，AF4 依赖于 CD133 表达的调节，这是 ALL 细胞生长所必需的。因此，CD133 可能代表了一部分癌症的治疗靶点。
