Scientific Publications

Identification of AML1-ETO Modulators with Chemical Genomics

Publication TypeWeb Article
Year of Publication2004
AuthorsCorsello, Steven M., Roti Giovanni, Ross Kenneth N., Chow Kwan T., Golub Todd R., and Stegmaier Kimberly
Last Update Dateunknown
AbstractSomatic rearrangements of transcription factors are a common abnormality in the acute leukemias. However, with rare exception, the resultant protein products have remained largely intractable as pharmacological targets. One example is AML1-ETO, the most common translocation reported in AML. We applied a genomic approach to chemically modulating AML1-ETO using gene expression signatures as surrogates for the expression versus loss of AML1-ETO in AML1-ETO expressing cells. Two top classes of compounds scored in a small molecule library screen: corticosteroids and dihydrofolate reductase inhibitors. Both classes of molecules induced loss of the AML-ETO signature, induced differentiation, inhibited cell viability, and induced apoptosis via on-target activity. The corticosteroids diminished AML1-ETO protein level, which was rescued via proteasome inhibition and glucocorticoid receptor antagonism. Furthermore, AML1-ETO expressing cell lines were exquisitely sensitive to the effects of corticosteroids on cellular viability compared to non-expressers, suggesting a possible role for corticosteroids in the treatment of patients with this genetic subtype of AML.