Ono Ryoichi, Masuya Masahiro, Ishii Satomi, Katayama Naoyuki, Nosaka Tetsuya
Department of Microbiology and Molecular Genetics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
Mol Cell Biol. 2017 Jun 15;37(13). doi: 10.1128/MCB.00585-16. Print 2017 Jul 1.
PLZF is a transcription factor that confers aberrant self-renewal in leukemogenesis, and the fusion gene causes acute promyelocytic leukemia (APL) through differentiation block. However, the molecular mechanisms of aberrant self-renewal underlying -mediated leukemogenesis are poorly understood. To investigate these mechanisms, comprehensive expression profiling of mouse hematopoietic stem/progenitor cells transduced with was performed, which revealed the involvement of a key transcriptional coactivator, Eya2, a target molecule shared by and , in the aberrant self-renewal. Indeed, as well as rendered those cells immortalized through upregulation of also led to immortalization without differentiation block, while depletion of suppressed clonogenicity in cells immortalized by without influence on differentiation and apoptosis. Interestingly, cancer outlier profile analysis of human samples of acute myeloid leukemia (AML) in The Cancer Genome Atlas (TCGA) revealed a subtype of AML that strongly expressed In addition, gene set enrichment analysis of human AML samples, including TCGA data, showed that this subtype of AML was more closely associated with the properties of leukemic stem cells in its gene expression signature than other AMLs. Therefore, EYA2 may be a target for molecular therapy in this subtype of AML, including APL.
PLZF是一种转录因子，在白血病发生过程中赋予异常的自我更新能力，而该融合基因通过分化阻滞导致急性早幼粒细胞白血病（APL）。然而，介导白血病发生的异常自我更新的分子机制尚不清楚。为了研究这些机制，对转导了的小鼠造血干细胞/祖细胞进行了全面的表达谱分析，结果显示关键转录共激活因子Eya2参与了异常自我更新，Eya2是和共有的一个靶分子。事实上，以及通过上调使这些细胞永生化，也导致细胞永生化而无分化阻滞，而敲除则抑制了由永生化的细胞的克隆形成能力，且不影响分化和凋亡。有趣的是，癌症基因组图谱（TCGA）中人类急性髓系白血病（AML）样本的癌症异常图谱分析揭示了一种强烈表达的AML亚型。此外，对包括TCGA数据在内的人类AML样本进行基因集富集分析表明，这种AML亚型在基因表达特征上比其他AML与白血病干细胞的特性更密切相关。因此，EYA2可能是这种AML亚型（包括APL）分子治疗的一个靶点。
