Mechanism of EVI1-induced Leukemogenesis

University Of Rochester, Rochester NY

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Abstract

DESCRIPTION (provided by applicant): Evil is a zinc finger gene that plays a regulatory role in hematopoiesis and a causative role in myeloid leukemia. We and others have shown that Evil has affects on cell proliferation, apoptosis, differentiation, and TGF? signaling. Using two different assays, we have shown that the ability of EVI1 to transform cells is strictly dependent on its ability to bind to DMA in a sequence-specific manner to a GACAAGATA-like motif. These findings imply that EVI1 binds to specific high-affinity sites in the genome and through this binding regulates a key set of target genes that are critical to its role in leukemogenesis. In a series of experiments using several complementary cell culture systems, we have identified some of these targets. They include genes involved in control of hematopoiesis (Gata2, Zfpm2/Fog2), apoptosis (Bcl2a1b, Dapk2), cell cycle (Ccnd2), and TGF? signaling (Skil). We hypothesize that EVI1 induces leukemia through the activation of cell proliferation and cell survival pathways, and that these effects are mediated through Gata2, a key downstream target of EVI1 and a critical regulator of hematopoiesis. To address this hypothesis, we propose three specific aims.