Abstract
Recurring chromosomal translocations observed in human leukemia often result in the expression of fusion proteins that are DNA-binding transcription factors. These altered proteins acquire new dimerization properties that result in the assembly of inappropriate multimeric transcription complexes that deregulate hematopoietic programs and induce leukemogenesis. Recently, we reported that the fusion protein AML1/MDS1/EVI1 (AME), a product of a t(3;21)(q26;q22) associated with chronic myelogenous leukemia and acute myelogenous leukemia, displays a complex pattern of self-interaction. Here, we show that the 8th zinc finger motif of MDS1/EVI1 is an oligomerization domain involved not only in interaction of AME with itself but also in interactions with the parental proteins, RUNX1 and MDS1/EVI1, from which AME is generated. Because the 8th zinc finger motif is also present in the oncoprotein EVI1, we have evaluated the effects of the interaction between RUNX1 and EVI1 in vitro and in vivo. We found that in vitro, this interaction alters the ability of RUNX1 to bind to DNA and to regulate a reporter gene, whereas in vivo, the expression of the isolated 8th zinc finger motif of EVI1 is sufficient to block the granulocyte colony-stimulating factor-induced differentiation of 32Dcl3 cells, leading to cell death. As EVI1 is not detected in normal bone marrow cells, these data suggest that its inappropriate expression could contribute to hematopoietic transformation in part by a new mechanism that involves EVI1 association with key hematopoietic regulators, leading to their functional impairment.
Highlights
Cellular transformation is mediated by the accumulation of genetic mutations, which change the biochemical properties or the level of expression of key factors in a progenitor cell
AML1/MDS1/ EVI1 (AME) is a fusion protein characterized by several structural motifs of the parental proteins, including the DNAbinding domain Runt of RUNX1 at the NH2 terminus; the PR domain of MDS1/ EVI1 (ME); the proximal zinc finger domain, containing seven motifs; and the distal zinc finger domain of ME formed by three motifs at the COOH terminus (Fig. 1A, line 3)
We report a novel interaction between RUNX1 and EVI1, two proteins that have been long associated with human leukemia
Summary
Cellular transformation is mediated by the accumulation of genetic mutations, which change the biochemical properties or the level of expression of key factors in a progenitor cell. The t(3;21)(q26;q22) detected in chronic myelogenous leukemia (CML) and myelodysplastic syndrome (MDS) fuses in frame the two conserved genes RUNX1, a member of the RUNX family, and MDS1/ EVI1 (ME), a member of the PR family [1, 2] This translocation is associated with very aggressive hematopoietic diseases and is characterized by the expression of the fusion gene AML1/MDS1/ EVI1 The isolated 8th zinc finger motif of EVI1 blocks by itself the differentiation of 32Dcl cells, leading to cell death Taken together, these results suggest that a mechanism by which EVI1 could contribute to the disruption of hematopoietic programs associated with leukemia is by interaction with RUNX1, which weakens its DNA-binding activity, leading to overall loss of RUNX1 function
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