As is the case with most human cancers, acute myeloid leukemia (AML) is the result of multiple genetic events, each of which leads to loss of a particular aspect of cellular growth control. Two key aspects of this loss of control involve unrestrained proliferation and a block to differentiation. While circumstantial support for the importance of the latter has come from the analysis of leukemic cell phenotype and the efficacy of differentiation therapy, we do not as yet have a clear molecular understanding of how this is manifested or caused. Evi-1 is a leukemogenic zinc finger transcriptional repressor that is thought to act by interfering with cellular maturation of myeloid cells. We have shown that Evi-1 can blunt the accumulation of C/ebpalpha mRNA during myelopoiesis; C/ebpalpha encodes a transcriptional regulatory protein that is essential for the generation of mature granulocytes. However, transcripts of other myeloid-essential regulatory proteins are unaffected by Evi-1. We therefore hypothesize that EVI-1 affects the expression of a very limited subset of genes that play a regulatory role in myeloid maturation. We further hypothesize that the repression of these genes by EVI-1 results in the block to differentiation. We will approach this by identifying and characterizing differences in transcription between Evi-1-expressing myeloid progenitor cells and control myeloid progenitor cells. The differentially expressed genes may be known or novel, and may be direct or indirect targets of Evi-1 action. Furthermore, we propose to test the importance of these transcriptional differences between Evi-1 expressing cells and control cells by assessing their ability to override the Evi-1 induced interference with myelopoiesis.
| Wilson, Michael; Tsakraklides, Vasiliki; Tran, Minh et al. (2016) EVI1 Interferes with Myeloid Maturation via Transcriptional Repression of Cebpa, via Binding to Two Far Downstream Regulatory Elements. J Biol Chem 291:13591-607 |
| Zhang, Yi; Stehling-Sun, Sandra; Lezon-Geyda, Kimberly et al. (2011) PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function. Blood 118:3853-61 |
| Boyd, Kathryn E; Xiao, Ying-Yi; Fan, Kai et al. (2006) Sox4 cooperates with Evi1 in AKXD-23 myeloid tumors via transactivation of proviral LTR. Blood 107:733-41 |
| Yatsula, B; Galvao, C; McCrann, M et al. (2006) Assessment of F-MuLV-induced tumorigenesis reveals new candidate tumor genes including Pecam1, St7, and Prim2. Leukemia 20:162-5 |
