Significant increase of self-renewal in hematopoietic cells after forced expression of EVI1

Abstract

EVI1 was first identified as a preferential integration site of ecotropic retroviruses in the MDS1/ EVI1 genomic locus leading to myeloid tumors in susceptible mice. Later studies showed that retroviral integration in the MDS1/EVI1 locus results in the emergence of a non-malignant dominant hematopoietic stem cell clone in non-susceptible mice strains, in non-human primates, and in patients, suggesting that a gene encoded by the locus could affect the self-renewal potential of a cell. The locus encodes two genes. One of them, EVI1, has long been associated with myeloid leukemia. To understand whether EVI1 has a role in self-renewal control, we forcibly expressed EVI1 in the bone marrow progenitors of two mice strains that differ in their proliferation and selfrenewal potential. By comparing the response of the hematopoietic cells to EVI1, we conclude that EVI1 has a role in prolonging the self-renewal potential of the cells and that this ability of EVI1 is limited and modulated by inherent characteristics of the cells.

EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization

“…Bone marrow cells from 5-fluorouracil-treated mice were transduced with Evi-1, and were subjected to colonyreplating assay (Figure 6a). Consistent with earlier reports, 29 primary bone marrow progenitors transduced with Evi-1, but not empty vector, formed colonies in methylcellulose that can be replated through at least seven rounds of culture (data not shown). Wright-Giemsa-stained cytospin preparations of the cells constituting these Evi-1-transduced colonies showed blastic morphology with myeloid dysplasia (Figure 6b).…”

EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia

“…Subsequently, the human EVI1 gene was detected in the breakpoint region of chromosome 3q26 rearrangements in different myeloid malignancies. 1 Additional evidence that EVI1 may act as an oncogene comes from studies by Laricchia-Robbio and Nucifora 35 and Kilbey et al 36 who showed that aberrant overexpression of EVI1 results in loss of cell-cycle control and increased self-renewal. Moreover, adult AML patients with high EVI1 expression, irrespective of harboring a 3q26 abnormality, have a poor prognosis.…”

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease

“…In addition to the role of EVI1 and MDS1−EVI1 in development, transcriptional regulation, self-renewal and cell cycle progression [44][45][46][47] , EVI1 has been shown to interact with proteins involved in the chromatin-remodeling process, including BRG1, SUV39H1, G9a and MBD3B, and may thereby influence proper centrosome replication, chromatin assembly and genomic stability [48][49][50][51][52] . During mitosis, centrosomes function as spindle poles, directing the formation of bipolar spindles, a process essential for accurate chromosome segregation 53 .…”

“…In our study, we observed profound clonal expansions driven by the insertional activation of EVI1, MDS1−EVI1 and PRDM16, a homolog of MDS1−EVI1, in multiple clones of both subjects 5 months after gene therapy. We detected no abnormalities in blood counts, bone marrow morphology or karyotype during this period, indicating that this insertional event was probably the driving event for progression toward clonal dominance.In addition to the role of EVI1 and MDS1−EVI1 in development, transcriptional regulation, self-renewal and cell cycle progression [44][45][46][47] , EVI1 has been shown to interact with proteins involved in the chromatin-remodeling process, including BRG1, SUV39H1, G9a and MBD3B, and may thereby influence proper centrosome replication, chromatin assembly and genomic stability [48][49][50][51][52] . During mitosis, centrosomes function as spindle poles, directing the formation of bipolar spindles, a process essential for accurate chromosome segregation 53 .…”