Document Detail


Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data.
MedLine Citation:
PMID:  18305216     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-02-27
Journal Detail:
Title:  Blood     Volume:  111     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-06-11     Completed Date:  2008-07-15     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5654-62     Citation Subset:  AIM; IM    
Affiliation:
James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, NY, USA.
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MeSH Terms
Descriptor/Qualifier:
Aldehydes / 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:
5T32-CA09363/CA/NCI NIH HHS; R01CA90446/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
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:
Blood. 2008 Jun 15;111(12):5423-4   [PMID:  18544693 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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