Dr. Shari Meyers' Research Focus

Major Research Interests:
Leukemogenesis; carcinogenesis; CBF-regulation of tissue-specific and cell-cycle gene transcription.

Research Program 1: Our first research interest focuses on understanding how the non-random chromosomal translocation, t(8;21), transforms myeloid cells. This work has significant relevance to human health issues. The t(8;21) is associated with 15% of acute myelogenous leukemia of the FAB M2 subtype and joins the Acute Myeloid Leukemia-1 gene (AML-1/RUNX1), on chromosome 21, to ETO (MTG8) on chromosome 8 to produce the tumor specific chimeric factor AML-1/ETO. AML-1 is normally expressed in hematopoietic cells and belongs to a family of transcription factors that is defined by the runt homology domain (rhd), a novel DNA binding motif. AML-1 activates transcription as part of a multi-protein complex and is required for normal hematopoiesis. AML-1/ETO retains the rhd and dominantly interferes with AML-1-mediated transcriptional activation of genes required for blood cell maturation. ETO does not itself bind to DNA but instead may function as a co-repressor. In support of this idea, ETO interacts with the co-repressor protein mSin3 and with histone deacetylase proteins. Thus it is likely that AML-1/ETO dominantly interferes with AML-1 gene regulation by recruiting histone deacetylase complexes to target promoters. ETO is nuclear matrix attached at sites co-incident with proteins involved in transcription repression (histone deacetylase-1, SMRT and mSin3). ETO also binds to site-specific transcription repressor proteins important in hematopoiesis such as PLZF and Gfi-1 (growth factor independence-1), supporting the notion that ETO is a co-repressor. These data suggest a complex model for the molecular basis of transformation by AML-1/ETO that must account for several functions attributable to ETO. First, AML-1/ETO interacts with histone deacetylase complexes through the ETO portion of the molecule. Second, ETO specifies a sub-nuclear address that is consistent with transcriptional repression and in effect "misroutes" the AML-1 DNA binding domain. Third, the ETO portion of AML-1/ETO mediates interactions with DNA binding proteins that play a role in hematopoietic cell survival and differentiation. These interactions may be critical to the selection of gene regulatory regions targeted by AML-1/ETO. We hypothesize that nuclear matrix-attachment and localization to ETO-specific addresses plays a role in transcriptional repression by AML-1/ETO. Because AML-1/ETO binds to Gfi-1 we hypothesize that AML-1/ETO could interact with Gfi-1 proteins in t(8; 21)-containing leukemia cells to further deregulate transcription.

Research Program 2: Our second research interest focuses on the role of the transcription factor complex Core Binding Factor (CBF) in prostate gene expression. CBF is a transcription factor complex consisting of one of a family of DNA binding proteins [RUNX1 (AML-1), RUNX2 (AML-3), or RUNX3 (AML-2)] and the unrelated, non-DNA binding protein CBFb. RUNX1 and RUNX2 are best known for their roles in leukemia and bone morphogenesis, respectively, where they regulate genes required for differentiation and cell cycle progression. Recently, RUNX2 was associated with the activation of the bone specific osteocalcin gene in a hormone independent prostate cancer cell line. Thus, aberrant activation of CBF occurs in prostate cancer cells and may lead to alterations in gene expression that contribute to the malignant phenotype. This project seeks to understand the role of CBF in prostate gene transcription by identifying the components of prostate CBF and testing these components for their effect on transcription of prostate-specific genes and genes regulating the prostate epithelial cell cycle. CBF activity has been characterized in prostate cancer cell lines and the CBF consensus site (TGTGGT) identified in the promoters/enhancers of the androgen regulated prostate specific antigen (PSA) and p21WAF1/CIP1 genes that encode a prostate-specific product and a cell cycle regulator, respectively. This study addresses three questions: (1) What are the components of CBF in prostate epithelial cells?, (2) What is the effect of RUNX1, RUNX2, or RUNX3 expression on transcriptional activity of the p21WAF1/CIP1 and PSA regulatory regions?, and (3) what is the physical and functional relationship between CBF and the androgen receptor (AR)? The studies are likely to provide essential knowledge concerning CBF- dependent gene regulation in prostate epithelial cells.