Drug resistance is the primary reason for treatment failure in patients with acute myeloid leukemia. Increased expression of MDR1 is the best characterized mechanism of resistance in this disease but little is known about the mechanisms regulating expression of this clinically important gene. To understand the development of drug resistance in hematopoietic malignancies, identification and characterization of the molecules which regulate expression of drug resistance genes is necessary. We hypothesize that EGR-1 mediates activation of the MDR1 promoter by Ras and induction of the MDR1 gene by ara-C.
Specific Aim 1 is to define the mechanism by which early growth response (EGR) transcription factors modulate MDR1 expression in hematopoietic cells.
Specific Aim 2 examines Ras activation of MDR1 transcription and determines if c-Ras is an intermediate in TPA mediated activation of the MDR1 promoter and expression of the endogenous MDR1 gene.
Specific aim 3 examines the mechanism of MDR1 gene induction by ara-C, a chemotherapeutic agent used in the treatment of AML, to determine if EGR-1 mediates this induction. The results of these studies will 1) determine how signals which regulate hematopoietic proliferation and differentiation contribute to MDR1 expression, and 2) define the mechanism of ara-C-induced MDR1 expression. The knowledge gained will help us to understand how growth regulatory signals control the expression of MDR1 in hematopoietic cells and how the chemotherapeutic agents used to treat leukemia may contribute to the emergence of a drug-resistant phenotype.
| McCoy, C; McGee, S B; Cornwell, M M (1999) The Wilms' tumor suppressor, WT1, inhibits 12-O-tetradecanoylphorbol-13-acetate activation of the multidrug resistance-1 promoter. Cell Growth Differ 10:377-86 |
