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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 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 Citation Map 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 Google Scholar Articles by Corsello, S. M. Articles by Stegmaier, K. PubMed PubMed Citation Articles by Corsello, S. M. Articles by Stegmaier, K. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Identification of AML1-ETO modulators by chemical genomics Steven M. Corsello1,*, Giovanni Roti1,*, Kenneth N. Ross2, Kwan T. Chow1, Ilene Galinsky3, Daniel J. DeAngelo3, Richard M. Stone3, Andrew L. Kung1, Todd R. Golub1,2,4, and Kimberly Stegmaier1,2 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, MA; 2 The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge; 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and 4 Howard Hughes Medical Institute, Chevy Chase, MD 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 pharmacologic targets. One example is AML1-ETO, the most common translocation reported in acute myeloid leukemia (AML). 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 with nonexpressers. 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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