|Publication Type||Journal Article|
|Year of Publication||2009|
|Authors||Corsello, SM, Roti, G, Ross, KN, Chow, KT, Galinsky, I, DeAngelo, DJ, Stone, RM, Kung, AL, Golub, TR, Stegmaier, K|
|Date Published||2009 Jun 11|
|Keywords||Acetylation, Animals, Antineoplastic Agents, Apoptosis, Cell Differentiation, Cell Proliferation, Combinatorial Chemistry Techniques, Core Binding Factor Alpha 2 Subunit, Flow Cytometry, Gene Expression Profiling, Genomics, Histone Deacetylase Inhibitors, Histone Deacetylases, Histones, Humans, Immunoblotting, Male, Mice, Mice, Inbred NOD, Myeloid Cells, Neoplasms, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Fusion, Pharmaceutical Preparations, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, RNA, Small Interfering, Translocation, Genetic|
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.
|PubMed Central ID||PMC2699238|
|Grant List||/ / Howard Hughes Medical Institute / United States|