EVI1 Impairs Myelopoiesis by Deregulation of PU.1 Function

Abstract

EVI1 is an oncogene inappropriately expressed in the bone marrow (BM) of f10% of myelodysplastic syndrome (MDS) patients. This disease is characterized by severe anemia and multilineage myeloid dysplasia that are thought to be a major cause of mortality in MDS patients. We earlier reported on a mouse model that constitutive expression of EVI1 in the BM led to fatal anemia and myeloid dysplasia, as observed in MDS patients, and we subsequently showed that EVI1 interaction with GATA1 blocks proper erythropoiesis. Whereas this interaction could provide the basis for the erythroid defects in EVI1-positive MDS, it does not explain the alteration of myeloid differentiation. Here, we have examined the expression of several genes activated during terminal myelopoiesis in BM cells and identified a group of them that are altered by EVI1. A common feature of these genes is their regulation by the transcription factor PU

Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors

“…This scan revealed significant (P < 0.0001) occurrence of 17 TF DNA binding motifs (Table S1). Two TFs previously reported as EVI1 interacting partners, GATA1 (27) and PU.1 (SPI1) (28), were among the overrepresented motifs. When we looked at the sequences of these 17 overrepresented TF motifs, we noticed that several were related to the EVI1 GATA or ETS-like motifs (Table S1).…”

The closely related rare and severe acute myeloid leukemias carrying EVI1 or PRDM16 rearrangements share singular biological features

“…At diagnosis, there were similar hemoglobin levels or white blood cell counts in both groups. Median platelet counts were 123x10 9 /L, higher than 100x10 9 /L in 53% of EVI1-r AML patients, compared to 25% in the control AML population (P=0.02). These subnormal counts were associated with platelets dysplasia (giant and hypogranular) in 57%.…”

“…Moreover, it indicates a very low rate of MPO expression in EVI1-r AML patients. It is interesting to note that relationships have been reported between EVI1 expression and MPO regulation, 8,9 suggesting that the translocation could interfere with MPO production in EVI1-r AML. Moreover, a mouse model has shown a relationship between EVI1 and thrombopoiesis, 10 indicating that the peculiar features of EVI1-r AML could be directly related to the abnormal expression of this gene.…”

Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins

“…Several groups reported that Evi1 blocks myeloid differentiation. [11][12][13] Evi1 also affects differentiation of erythroid and megakaryocytic cells. 11,[14][15][16] In addition to its DNA-binding activity, Evi1 has the potential to recruit diverse proteins for transcriptional regulation.…”