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

Abstract

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). © 2009 Japanese Cancer Association.