Notably, reduced GATA2 expression suppresses the differentiation but promotes the proliferation of EVI1-expressing leukemic cells, which accelerates EVI1-driven leukemogenesis.
3q26.2/EVI1 rearrangements resulting in EVI1 overexpression play an important role in leukemogenesis and are associated with treatment resistance and a poorer prognosis in patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and BCR-ABL negative myeloproliferative neoplasms.
In this study, we identified a mechanism whereby a GATA2 distal hematopoietic enhancer (G2DHE or -77-kb enhancer) is brought into close proximity to the EVI1 gene in inv(3)(q21;q26) inversions, leading to leukemogenesis.
As activation of Evi1 has been shown to coincide with NRAS mutations in human acute myeloid leukemia, our murine model recapitulates crucial events in human leukemogenesis.
Its role in leukemogenesis is still unclear but it is thought that overall EVI1 can act mostly as a transcription repressor through its interaction with a subset of histone deacetylases.
In keeping with findings in other recurrent 3q26 rearrangements, overexpression of the EVI1 gene appears to be the major contributor to leukemogenesis in patients with a t(3;17).
These results suggest that EVI1 overexpression was the major factor contributing to leukemogenesis, and the late appearance of the Ph chromosome is closely associated with the progression to an aggressive form of leukemia.
This identifies a novel function of Evi-1 as a member of corepressor complexes and suggests that aberrant recruitment of corepressors is one of the mechanisms involved in Evi-1-induced leukemogenesis.
This identifies a novel function of Evi-1 as a member of corepressor complexes and suggests that aberrant recruitment of corepressors is one of the mechanisms for Evi-1-induced leukemogenesis.
This may be the first case among the therapy-related cases of MDS/AML reported whose karyotypes were followed and in which the mRNA expression of EVI 1 gene involved was directly proved in the leukemogenesis process of chemotherapy-induced secondary MDS and AML.
We are beginning to characterize candidate target genes located in the mouse genome near EVI1 binding sites with the expectation that these will yield insight into EVI1 function both in normal cells and in leukemogenesis.
It should, therefore, be useful both for studying the biological characteristics of acute myelogenous leukemia M0 subtype and for investigating the role of the EVI1 gene in leukemogenesis.
Interestingly, Fim-3 is tightly linked to Evi-1, another common integration site of ecotropic virus involved in another model of mouse myeloid leukemogenesis.