Regulation of transcription and analysis of drug targets in lymphoma and myeloma cells

Abstract

Hematological malignancies, such as lymphomas and myelomas, have low cure rates or remain refractory to treatment, although advances have been made in treatment regimens for these patients. Questions still remain as to what is occurring in these cells on a molecular level, specifically at the level of gene transcription. The positive regulatory domain I binding factor 1 (PRDI-BF1) has been shown to directly repress genes required for cell proliferation and maintenance of the B cell phenotype, however very little is known as to its regulation. The first study presented in this dissertation demonstrates regulation of the PRDM1 gene occurs primarily at the level of transcription in B cell receptor (BCR)-stimulated lymphoma cells and myeloma cells. It also demonstrates PU.1 binding is involved in BCR-mediated activation of lymphoma cells. Most importantly, this study presents evidence of a promoter poised and primed for activation in lymphoma cells. These studies lay the groundwork for the second study which examines modulation of PRDM1 expression in lymphoma cells by chemotherapeutic agents. Induction of PRDI-BF1 in lymphoma cells negative for PRDM1 gene expression correlates with increased apoptosis, which has important therapeutic implications for treatment of lymphomas. One common problem that arises in treatment of cancer patients is the eventual emergence of a drug resistant population of cells. Identifying specific drug targets and whether they confer drug resistance is an important area of study, which is the focus of the third study presented in this dissertation. It demonstrates the response of myeloma cells to treatment with the farnesyltransferase inhibitor (FTI)-277 and examines whether known mechanisms of drug resistance in these cells are responsible for cross-resistance to FTI-277