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PLZF is a transcription factor that confers aberrant self-renewal in leukemogenesis, and thePLZF-RARA fusion gene causes acute promyelocytic leukemia (APL) through differentiation block. However, the molecular mechanisms of aberrant self-renewal underlyingPLZF -mediated leukemogenesis are poorly understood. To investigate these mechanisms, comprehensive expression profiling of mouse hematopoietic stem/progenitor cells transduced withPlzf was performed, which revealed the involvement of a key transcriptional coactivator, Eya2, a target molecule shared byPlzf andPLZF-RARA , in the aberrant self-renewal. Indeed,PLZF-RARA as well asPlzf rendered those cells immortalized through upregulation ofEya2. Eya2 also led to immortalization without differentiation block, while depletion ofEya2 suppressed clonogenicity in cells immortalized byPLZF-RARA 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 expressedEYA2 . 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, includingPLZF-RARA APL.

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis