DEREGULATION OF MYELOPOIESIS BY ZINC FINGER PROTEIN EVI1

Yale University, New Haven CT

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Abstract

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.