Lo Miao-Chia, Peterson Luke F
Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
Crit Rev Eukaryot Gene Expr. 2013;23(2):103-13. doi: 10.1615/critreveukaryotgeneexpr.2013006917.
Microarray technology has contributed valuable information to gene expression signatures of leukemia and other types of cancers and helped to identify biological markers and potential therapeutic targets for treating these diseases. Acute myeloid leukemia (AML) is often caused by aberrant fusion transcription factors resulting from chromosomal translocations, and the dysregulated genes detected by microarray include both direct and indirect targets of the oncogenic transcription factors. The ChIP-chip technology enables the identification of direct targets of a transcription factor based on its promoter occupancy and cellular context. Using AML1-ETO9a-induced AML as a cancer model and using a combined gene expression and promoter occupancy profiling approach, we recently identified CD45 as a direct down-regulated target of t(8;21) fusion proteins. This finding subsequently led us to discover the enhanced Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, which is negatively regulated by CD45, in t(8;21) AML. This review summarizes the background of t(8;21) leukemia, structural features of the translocation fusion proteins, and the merits of combining gene discovery technologies for the identification of therapeutic targets in t(8;21) leukemia.
微阵列技术为白血病及其他类型癌症的基因表达特征提供了有价值的信息，并有助于识别治疗这些疾病的生物标志物和潜在治疗靶点。急性髓系白血病（AML）通常由染色体易位产生的异常融合转录因子引起，通过微阵列检测到的失调基因包括致癌转录因子的直接和间接靶点。染色质免疫沉淀芯片（ChIP-chip）技术能够基于转录因子对启动子的占据情况和细胞环境来识别其直接靶点。我们最近以AML1-ETO9a诱导的AML作为癌症模型，采用基因表达和启动子占据情况分析相结合的方法，将CD45鉴定为t(8;21)融合蛋白的直接下调靶点。这一发现随后使我们在t(8;21) AML中发现了由CD45负调控的增强型Janus激活激酶（JAK）/信号转导及转录激活因子（STAT）信号通路。本综述总结了t(8;21)白血病的背景、易位融合蛋白的结构特征，以及结合基因发现技术来识别t(8;21)白血病治疗靶点的优点。
