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.

Fig. 1. Schematic of the MDS and EVI1 (MECOM) locus proteins.

C2H2-zinc finger motifs are shown in blue. Zinc finger motifs 1–7 and motifs 8–10 form the N-terminal and C-terminal zinc finger domains respectively. The repressive domain and acidic domain are depicted in tan and red, respectively. The numbers beneath the schematic indicate the amino acid positions of the zinc finger domains, the repressive domain and the acidic domain of EVI1.

Fig. 2. Schematic representation of the 318-bp minimal promoter of EVI1 in humans.

Within the upstream EVI1 promoter, the positions and nucleotide sequences/binding sites of specific transcription factors are shown.

Fig. 3. Schematic of the q21-26 locus on chromosome 3 in normal cells and cells with inv(3)(q21q26) or t(3;3)(q21q26).

In both inv(3)(q21q26) or t(3;3)(q21q26), the breakpoints lead to juxtaposition of a region surrounding the distal GATA2 enhancer and the RPN1 gene in 3q21 with the EVI1 gene in 3q26. Breakpoints occur 3′ of the EVI1 gene in the inv(3)(q21q26) setting, whereas they occur 5′ of the EVI1 gene in the case of t(3;3)(q21q26). In both types of 3q21q26 rearrangement, the GATA2 enhancer induces EVI1 gene transcription instead of GATA2 expression and thus promotes leukemogenesis.

Fig. 4. EVI1 and EVI1 fusion proteins.

Schematic diagram of the EVI1, MDS1, MDS1-EVI1, RUNX1, RUNX1-MDS1-EVI1, ETV6, ETV6-EVI1, and ETV6-MDS1-EVI1 proteins.

Fig. 5. Effects of targeting EVI1 transcription and activity in MDS/AML with BET inhibitors.

In AML cells with inv(3)(q21q26) or t(3;3)(q21q26), the hijacked GATA2 enhancer interacts with the EVI1 promoter resulting in high expression of EVI. This leads to aberrant regulation of multiple transcriptional programs including metabolism, stem cell phenotype, growth/survival, environmental interactions, and immune surveillance in AML cells. Treatment with BET inhibitors that evict BET proteins such as BRD4 from the chromatin of the GATA2 enhancer leads to downregulation of EVI1 and its activity in AML cells.