Document Detail


A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia.
MedLine Citation:
PMID:  20508621     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges as a consequence of the t(15;17) translocation, acts as a transcriptional repressor that blocks neutrophil differentiation at the promyelocyte (PM) stage. In this study, we used publicly available microarray data sets and identified signatures of genes dysregulated in APL by comparison of gene expression profiles of APL cells and normal PMs representing the same stage of differentiation. We next subjected our identified APL signatures of dysregulated genes to a series of computational analyses leading to (i) the finding that APL cells show stem cell properties with respect to gene expression and transcriptional regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost. In a broader perspective, our study provides strong evidence that genomic strategies might be used in a clinical setting to prospectively identify candidate drugs that subsequently are validated in vitro to define the most effective drug combination for individual cancer patients on a rational basis.
Authors:
T T Marstrand; R Borup; A Willer; N Borregaard; A Sandelin; B T Porse; K Theilgaard-Mönch
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-27
Journal Detail:
Title:  Leukemia     Volume:  24     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-14     Completed Date:  2010-10-07     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1265-75     Citation Subset:  IM    
Affiliation:
Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Cells, Cultured
Gene Expression Profiling
Granulocyte Precursor Cells / drug effects
Humans
Leukemia, Promyelocytic, Acute / drug therapy,  genetics*,  metabolism
Oligonucleotide Array Sequence Analysis
Tretinoin / pharmacology*
Tumor Markers, Biological / genetics*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Tumor Markers, Biological; 302-79-4/Tretinoin

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


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