Identification of AML1-ETO Modulators by Chemical Genomics

Blood. 2009 Jun 11;113(24):6193-205. Epub 2009 Apr 17.. Published: 2009.06.10

Steven M. Corsello, Giovanni Roti, Kenneth N. Ross, Kwan T. Chow, Ilene Galinsky, Richard M. Stone, Daniel J. DeAngelo, Andrew N. Kung, Todd R. Golub, and Kimberly Stegmaier

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Abstract

Somatic rearrangements of transcription factors are common abnormalities in the acute leukemias. With rare exception, however, the resultant protein products have remained largely intractable as pharmacological targets. One example is AML1-ETO, the most common translocation reported in AML. In order to identify AML1-ETO modulators, we screened a small molecule library using a chemical genomic approach. Gene expression signatures were used as surrogates for the expression versus loss of the translocation in AML1-ETO-expressing cells. The top classes of compounds that scored in this screen were corticosteroids and dihydrofolate reductase (DHFR) inhibitors. In addition to modulating the AML1-ETO signature, both classes induced evidence of differentiation, dramatically inhibited cell viability, and ultimately induced apoptosis via on-target activity. Furthermore, AML1-ETO-expressing cell lines were exquisitely sensitive to the effects of corticosteroids on cellular viability compared to non-expressers. The corticosteroids diminished AML1-ETO protein in both cell lines and primary patient cells, which was rescued via proteasome inhibition and glucocorticoid receptor antagonism. Moreover, these molecule classes demonstrated synergy in combination with standard AML chemotherapy agents and activity in an orthotopic model of AML1-ETO-positive AML. This work suggests a possible role for DHFR inhibitors and glucocorticoids in treating patients with AML1-ETO-positive disease.

Keywords: AML cancer chemical genomics leukemia small molecule library screen

Supplemental Data

Description Link/Filename
Text file describing supplemental information contents README.AE
Supplementary Tables and Figures Corsello_SupplementaryTablesFigures.pdf
Supplementary Methods Corsello_SupplementaryMethods.pdf
Kasumi AML1-ETO Knockdown Data Kasumi_AML1-ETO_complete_200410.res
U937 AML1-ETO Induced Data U937_AMLeto_inducible_ams.res
Kasumi AML1-ETO Knockdown Data CEL Files Kasumi_AML1-ETO_CelFiles_080505.zip
U937 AML1-ETO Induced Data CEL Files U937_AML1-ETO_Induce_CelFiles_080505.zip