EVI1 dysregulation: impact on biology and therapy of myeloid malignancies

Abstract

Ecotropic viral integration site 1 (Evi1) was discovered in 1988 as a common site of ecotropic viral integration resulting in myeloid malignancies in mice. EVI1 is an oncogenic zinc-finger transcription factor whose overexpression contributes to disease progression and an aggressive phenotype, correlating with poor clinical outcome in myeloid malignancies. Despite progress in understanding the biology of EVI1 dysregulation, significant improvements in therapeutic outcome remain elusive. Here, we highlight advances in understanding EVI1 biology and discuss how this new knowledge informs development of novel therapeutic interventions. EVI1 is overexpression is correlated with poor outcome in some epithelial cancers. However, the focus of this review is the genetic lesions, biology, and current therapeutics of myeloid malignancies overexpressing EVI1.

EVI1 Promotes the Proliferation and Invasive Properties of Human Head and Neck Squamous Cell Carcinoma Cells

“…EVI1 exerts its biological functions primarily by acting as a transcription factor [3,4,[6][7][8][9][10][11][12]. We therefore aimed to identify putative EVI1 target genes in HNSCC cells.…”

“…Ecotropic viral integration site 1 (EVI1), one of several transcript and protein variants derived from the MDS1-EVI1 complex (MECOM, alias PRDM3) locus in chromosome band 3q26 [3,4], was first discovered because its transcriptional activation by retroviral insertion promoted myeloid leukemia in mice [5]. EVI1 is a transcription factor with two zinc finger domains, comprising seven and three zinc finger motifs, respectively [3,4].…”

“…Ecotropic viral integration site 1 (EVI1), one of several transcript and protein variants derived from the MDS1-EVI1 complex (MECOM, alias PRDM3) locus in chromosome band 3q26 [3,4], was first discovered because its transcriptional activation by retroviral insertion promoted myeloid leukemia in mice [5]. EVI1 is a transcription factor with two zinc finger domains, comprising seven and three zinc finger motifs, respectively [3,4]. It has been shown to bind to DNA in a sequence-specific manner, to interact both with other sequencespecific transcription factors and with transcriptional cofactors, and to regulate numerous target genes [3,4,[6][7][8][9][10][11][12].…”

“…EVI1 is a transcription factor with two zinc finger domains, comprising seven and three zinc finger motifs, respectively [3,4]. It has been shown to bind to DNA in a sequence-specific manner, to interact both with other sequencespecific transcription factors and with transcriptional cofactors, and to regulate numerous target genes [3,4,[6][7][8][9][10][11][12]. Targeted disruption of the Mecom locus in mice revealed multiple roles in embryonic development [13].…”

PRMT5 regulates ATF4 transcript splicing and oxidative stress response

“…To better understand the mechanistic role of PRMT5, we investigated downstream transcriptome regulation by PRMT5, focusing on poor prognosis forms of AML that are dependent on PRMT5 function. One such subclass of AML has a rearrangement of chromosome 3q21 and is dependent on ecotropic virus integration site 1 (EVI1) factor-driven gene expression programs affecting stemness, apoptotic response, and differentiation [ [25] , [26] , [27] ]. In this group of AML, our transcriptomic analysis identified activating transcription factor 4 (ATF4) as a PRMT5 target.…”