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Identification of AML1-ETO Modulators with Chemical Genomics

Publication TypeWeb Article
Year of Publication2004
AuthorsCorsello, SM, Roti, G, Ross, KN, Chow, KT, Golub, TR, Stegmaier, K
Last Update Dateunknown

Somatic 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.