Eya2 Is Critical For The E2a-Hlf-Mediated Immortalization Of Mouse Hematopoietic Stem/Progenitor Cells

The immunoglobulin enhancer-binding factor/hepatic leukemia factor (E2A-HLF) oncogenic fusion gene, generated by t(17;19)(q22;p13) translocation in childhood B-cell acute lymphoblastic leukemia with a very poor prognosis, encodes a chimeric transcription factor in which the transactivation domains of E2A are fused to the DNA-binding and dimerization domain of HLF. E2A-HLF has been demonstrated to have an anti-apoptotic effect. However, the molecular mechanism underlying E2A-HLF-mediated leukemogenesis remains unclear. The present study identified EYA transcriptional coactivator and phosphatase 2 (Eya2), the forced expression of which is known to immortalize mouse hematopoietic stem/progenitor cells (HSPCs), as a direct target molecule downstream of E2A-HLF. E2A-HLF-immortalized mouse HSPCs expressed Eya2 at a high level in the aberrant self-renewal program. Chromatin immunoprecipitation-quantitative polymerase chain reaction and a reporter assay revealed that E2A-HLF enhanced the Eya2 expression by binding to the promoter region containing the E2A-HLF-binding consensus sequence. Eya2 knockdown in E2A-HLF-immortalized cells resulted in reduced colony-forming efficiency. These results suggest a critical role of Eya2 in E2A-HLF-mediated leukemogenesis.