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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6193-6205. Prepublished online as a Blood First Edition Paper on April 17, 2009; DOI 10.1182/blood-2008-07-166090. This Article Full Text (PDF) Supplemental Methods, Tables, and Figures Additional Supplemental Figures All Versions of this Article: blood-2008-07-166090v1 113/24/6193    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Corsello, S. M. Articles by Stegmaier, K. Search for Related Content PubMed PubMed Citation Articles by Corsello, S. M. Articles by Stegmaier, K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 8, 2008 Accepted March 28, 2009 Identification of AML1-ETO modulators by chemical genomics Steven M. Corsello, Giovanni Roti, Kenneth N. Ross, Kwan T. Chow, Ilene Galinsky, Daniel J. DeAngelo, Richard M. Stone, Andrew L. Kung, Todd R. Golub, and Kimberly Stegmaier* Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA, United States The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, United States Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States Howard Hughes Medical Institute, Boston, MA, United States * Corresponding author; email: kimberly_stegmaier{at}dfci.harvard.edu. 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 AML cells in a proteasome- and glucocorticoid receptor-dependent manner. 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 role for DHFR inhibitors and corticosteroids in treating patients with AML1-ETO-positive disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. M. Stone and D. J. DeAngelo Screens, iron, and leukemia Blood, October 1, 2009; 114(14): 2857 - 2858. [Full Text] [PDF]

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