Oncogene addiction of ATL cells and abnormal Polycomb-miRNA-signal transduction

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Based on our comprehensive dataset from ATL patient samples, we addressed the exact molecular mechanism of ATL, which should be targeted in clinical regimens. Using a microarray technique, we identified leukemic cell-specific gene expression pattern. In addition, we revealed activation of p38 and Hedgehog signaling pathways, which supported pro-survival capability.We performed global histone methylation profiling of patient-derived primary ATL cells. We successfully detected the numerous gene promoters with aberrant repressive H3K27me3 mark in ATL cells. Interestingly, Tax-triggered immortalizing cells partially mimicked the methylation pattern observed in ATL cells. In parallel, we identified an intimate relationship between NF-kB signaling and EZH2. Despite the absence of EZH2 active mutation observed in DLBCL, EZH2 inhibitors significantly killed patient ATL cells. Our findings indicate that ATL is characterized by EZH2-dependent robust and global epigenetic rearrangement.