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.