Myeloid Leukemia Oncogene Evi 1
Role of Evi1 in Leukemogenesis
The Evi1 locus plays an important role in human and mouse leukemia (reviewed in Hirai, Izutsu, et al., 2001) as well as normal mammalian development (Perkins, Mercer, et al., 1991; Hoyt, Bartholomew, et al., 1997). The gene encodes a series of protein isoforms that variably contain up to ten C2H2 zinc fingers as well as a repression domain that binds CtBP (Turner and Crossley, 1998), consistent with its demonstrated role in transcriptional repression (Bartholomew, Kilbey, et al., 1997). The most well studied of the EVI1 isoforms is the 125 kDa isoform that contains ten zinc fingers split into clusters of 7 and 3, at the N- and C-terminal ends of the protein. This isoform binds to DNA in a sequence-specific manner via the first and second zinc finger domains (Perkins, Fishel, et al., 1991; Funabiki, Kreider, et al., 1994). The binding to DNA via the first set of fingers is highly specific (Perkins and Kim, 1996) and candidate target genes have been reported (Kim, Hui, et al., 1998). The significance of these has not been confirmed, nor has it been clearly shown that leukemogenicity is dependent on DNA binding.
The mechanism by which Evi1 induces leukemia is not known. Evidence has been found for four different effects of Evi1 expression on cell growth. Several studies have shown that Evi1 overexpression can interfere with myeloid maturation, and in this way likely contributes to the leukemia phenotype. In 32Dcl3 cells, treatment with G-CSF leads to differentiation into mature granulocytes; transduction of 32Dcl3 cells with retrovirus encoding the 125 kDa isoform resulted in cells that failed to respond to G-CSF and underwent cell death (Morishita, Parganas, et al., 1992). However, subsequently it was shown that 32Dcl3 cells have a proviral insertion at the endogenous Evi1 locus and overexpress multiple EVI1 isoforms (Khanna-Gupta, Lopingco, et al., 1996). It is likely that activation of Evi1 contributes to immortalized growth of the cell line, perhaps by preventing spontaneous differentiation. However, the cell line still responds to G-CSF, and thus clearly Evi1 expression in this cell line does not completely abrogate responsiveness to cytokine-induced differentiation. The fact that further overexpression causes a loss of responsiveness to G-CSF indicates that a threshold exists for the biological effects of Evi1 in myeloid cells.
Sox4 cooperates with Evi1 in AKXD-23
myeloid tumors via transactivation
of proviral LTR
Sources of Funding
NIH R01 CA112188
Bartholomew, C., A. Kilbey, et al. (1997). “The Evi-1 proto-oncogene encodes a transcriptional repressor activity associated with transformation.” Oncogene 14: 569-577.
Funabiki, T., B. L. Kreider, et al. (1994). “The carboxyl domain of zinc fingers of the Evi-1 myeloid transforming gene binds a consensus sequence GAAGATGAG.” Oncogene 9: 1575-1581.
Hirai, H., K. Izutsu, et al. (2001). “Oncogenic mechanisms of Evi-1 protein.” Cancer Chemother Pharmacol 48 (Suppl 1): S35-S40.
Hoyt, P., C. Bartholomew, et al. (1997). “The Evi1 proto-oncogene is required at midgestation for neural, heart, and paraxial mesenchyme development.” Mechanisms of Development 65: 55-70.
Khanna-Gupta, A., M. Lopingco, et al. (1996). “Retroviral insertional activation of the Evi1 oncogene does not prevent G-CSF-induced maturation of the murine pluripotent myeloid cell line, 32DCl3.” Oncogene 12: 563-569.
Kim, J., P. Hui, et al. (1998). “Identification of candidate target genes for EVI1, a zinc finger oncoprotein, using a novel selection strategies.” Oncogene 17: 1527-1538.
Morishita, K., E. Parganas, et al. (1992). “Expression of the Evi-1 zinc finger gene in 32Dcl3 myeloid cells blocks granulocytic differentiation in response to granulocyte colony-stimulating factor.” Mol Cell Biol 12: 183-189.
Perkins, A. and J. Kim (1996). “Zinc fingers 1-7 of EVI1 fail to bind to the GATA motif by itself but require the core site GACAAGATA for binding.” J. Biol. Chem 271: 1104-1110.
Perkins, A. S., R. Fishel, et al. (1991). “Evi-1, a murine zinc finger proto-oncogene, encodes a sequence-specific DNA-binding protein.” Mol Cell Biol 11: 2665-2674.
Perkins, A. S., J. A. Mercer, et al. (1991). “Patterns of Evi-1expression in embryonic and adult tissues suggest that Evi-1 plays an important role in mouse development.” Development 111: 479-487.
Turner, J. and M. Crossley (1998). “Cloning and characterization
of mCtBP2, a co-repressor that associates with basic Kruppel-like
factor and other mammalian transcriptional regulators.” EMBO
J 17: 5129-5140.