MDS1/EVI1 enhances TGF-beta1 signaling and strengthens its growth-inhibitory effect but the leukemia-associated fusion protein AML1/MDS1/EVI1, product of the t(3;21), abrogates growth-inhibition in response to TGF-beta1.
EVI-1 (ecotropic virus integration site-1) was at first identified as an integration site of the murine leukemia retrovirus in murine myeloid leukemias.
Although it is unlikely that the Rb gene is directly involved in this translocation, the loss of the Rb gene product combined with the activation of the EVI1 gene may have led to the development of leukemia.
Characterization of the RUNX1-PRDM16 fusion protein and comparison with the RUNX1-MDS1/EVI1 protein will facilitate the understanding of the mechanisms underlying RUNX1-associated leukemia.
Experimental overexpression of EVI1 by itself was insufficient to cause leukemia in animal model systems, but it cooperated with other genes in this process.
Here, we review the current understanding of the role of Evi1 in controlling the development of leukemia and highlight potential modalities for targeting factors involved in Evi1-regulated signaling.
High EVI1 expression was detected mainly in myelomonocytic-lineage (designated as e-M4/M5 subtype) leukemia with MLL rearrangements and in megakaryocytic-lineage (designated as e-M7 subtype) leukemia, and its prognostic association was observed in the e-M4/M5 subtype but not in the e-M7 subtype.
However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors.
In contrast, EVI-1 is barely expressed in normal hematopoietic cells, but it is overexpressed in chronic myelocytic leukemia in blastic crisis and myelodysplastic syndrome-derived leukemia.
In this paper, we have analyzed chromosomal rearrangements in two leukemia cell lines derived from CML-BC with inv(3)(q21q26) and have identified the breakpoints within the EVI1 coding area.
Our results suggest that the leukemogenic role of EVI1 expression may differ between post-MDS AML and leukemia, with EVI1 expression associated with a 3q26 abnormality.
Overexpression of EVI-1 also occurs with high frequency in leukemia patients without 3q26 abnormalities, and importantly, high EVI-1 expression is an independent negative prognostic indicator irrespective of the presence of 3q26 rearrangements.
Specific gene activation (N-myc, evi-1) or fusion genes such as the alpha retinoic acid receptor (alpha RAR) and pml have been identified as the specific cause of some cases of leukemia.