Pathogenetic significance of ecotropic viral integration site‐1 in hematological malignancies

The ecotropic viral integration site‐1 (Evi‐1) gene was first identified as a common locus of retroviral integration in murine leukemia models. In humans, EVI‐1 is located on chromosome 3q26, and rearrangements on chromosome 3q26 often activate EVI‐1 expression in hematological malignancies. Overexpression of EVI‐1 also occurs with high frequency in leukemia patients without 3q26 abnormalities, and importantly, high EVI‐1 expression is an independent negative prognostic indicator irrespective of the presence of 3q26 rearrangements. Recent gene targeting studies in mice revealed that Evi‐1 is preferentially expressed in hematopoietic stem cells and plays an essential role in proliferation and maintenance of hematopoietic stem cells. In addition, intense attention has been focused on the EVI‐1 gene complex as retrovirus integration sites because transcription‐activating integrations into the EVI‐1 locus confer survival and self‐renewing ability to hematopoietic cells. The experimental results using animal models suggest that activation of Evi‐1 in hematopoietic cells leads to clonal expansion or dysplastic hematopoiesis, whereas onset of full‐blown leukemia requires cooperative genetic events. EVI‐1 possesses diverse functions as an oncoprotein, including suppression of transforming growth factor‐β‐mediated growth inhibition, upregulation of GATA2, inhibition of the Jun kinase pathway, and stimulation of cell growth via activator protein‐1. In this article, we summarize current knowledge regarding the biochemical properties and biological functions of EVI‐1 in normal and malignant hematopoiesis, with specific focus on its pathogenetic significance in hematological malignancies. (Cancer Sci 2009; 100: 990–995)