| Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. | |
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MedLine Citation:
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PMID: 18305216 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Increasing evidence indicates that malignant stem cells are important for the pathogenesis of acute myelogenous leukemia (AML) and represent a reservoir of cells that drive the development of AML and relapse. Therefore, new treatment regimens are necessary to prevent relapse and improve therapeutic outcomes. Previous studies have shown that the sesquiterpene lactone, parthenolide (PTL), ablates bulk, progenitor, and stem AML cells while causing no appreciable toxicity to normal hematopoietic cells. Thus, PTL must evoke cellular responses capable of mediating AML selective cell death. Given recent advances in chemical genomics such as gene expression-based high-throughput screening (GE-HTS) and the Connectivity Map, we hypothesized that the gene expression signature resulting from treatment of primary AML with PTL could be used to search for similar signatures in publicly available gene expression profiles deposited into the Gene Expression Omnibus (GEO). We therefore devised a broad in silico screen of the GEO database using the PTL gene expression signature as a template and discovered 2 new agents, celastrol and 4-hydroxy-2-nonenal, that effectively eradicate AML at the bulk, progenitor, and stem cell level. These findings suggest the use of multicenter collections of high-throughput data to facilitate discovery of leukemia drugs and drug targets. |
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Authors:
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Duane C Hassane; Monica L Guzman; Cheryl Corbett; Xiaojie Li; Ramzi Abboud; Fay Young; Jane L Liesveld; Martin Carroll; Craig T Jordan |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-02-27 |
Journal Detail:
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Title: Blood Volume: 111 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2008 Jun |
Date Detail:
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Created Date: 2008-06-11 Completed Date: 2008-07-15 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 5654-62 Citation Subset: AIM; IM |
Affiliation:
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James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, NY, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aldehydes
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pharmacology Animals Anti-Inflammatory Agents, Non-Steroidal / chemistry, pharmacology Antineoplastic Agents / pharmacology* Cell Death / drug effects Cysteine Proteinase Inhibitors / pharmacology Databases, Genetic Gene Expression Profiling* Gene Expression Regulation, Leukemic / drug effects Humans Leukemia, Myeloid, Acute / drug therapy*, pathology Mice Mice, Inbred NOD Mice, SCID Models, Genetic Neoplastic Stem Cells / drug effects*, pathology, physiology Oligonucleotide Array Sequence Analysis Sesquiterpenes / chemistry, pharmacology Terpenes / pharmacology Triterpenes / pharmacology Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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5T32-CA09363/CA/NCI NIH HHS; R01CA90446/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Aldehydes; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Antineoplastic Agents; 0/Cysteine Proteinase Inhibitors; 0/Sesquiterpenes; 0/Terpenes; 0/Triterpenes; 29343-52-0/4-hydroxy-2-nonenal; 29552-41-8/parthenolide; 34157-83-0/tripterine |
| Comments/Corrections | |
Comment In:
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Blood. 2008 Jun 15;111(12):5423-4
[PMID:
18544693
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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