Differentiation of leukemic cells represents an attractive, but largely unproven therapy for the myeloid leukemias. We have shown that mithramycin is able to induce differentiation of blast phase chronic myelogenous leukemia (CML) cells in vitro and in vivo, and is an effective agent in certain patients with blast phase CML. Mithramycin selectively inhibits expression of the c-myc and c-abl genes, as well as other genes with G-C rich promoter sequences. We have shown that this drug binds to G-C rich regions of the c-myc promoter, preventing binding of putative regulatory proteins and inactivating promoter function. We intend to extend these studies to investigate the potential mechanism by which RNA synthesis inhibition induces myeloid differentiation.
The specific aims of this proposal are: 1. To determine whether other G-C specific DNA binding drugs have the same DNA binding sites in the c-myc promoter, and the same effect in vivo. 2. To determine whether inhibition of c-myc expression is critical in the induction of myeloid differentiation by mithramycin. 3. To determine whether mithramycin also inhibits formation of the transcription initiation complex and expression of the abl/bcr gene in CML cells. 4. To determine whether mithramycin selectively inhibits c-myc expression by preventing binding of a specific c-myc regulatory protein. 5. To determine whether resistance and/or lack of response to mithramycin may reflect increased expression of the multidrug resistance (mdr) gene. The results of the proposed experiments will enable us to begin to understand whether selective alteration of gene expression may allow us to modulate the leukemic phenotype. They will also allow us to use mithramycin as a prototype of a DNA binding drug to study the effect of specific transcriptional changes on the behavior of malignant cells, and the possible utility of such approaches to the treatment of malignant diseases.
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