Document Detail

Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity.
MedLine Citation:
PMID:  17218384     Owner:  NLM     Status:  MEDLINE    
Disease relapse sometimes occurs after acute promyelocytic leukemia (APL) therapy with all-trans retinoic acid (ATRA). Among the diagnostic parameters predicting relapse, heterogeneity in the in vitro differentiation rate of blasts is an independent factor. To identify biologic networks involved in resistance, we conducted pharmacogenomic studies in APL blasts displaying distinct ATRA sensitivities. Although the expression profiles of genes invested in differentiation were similarly modulated in low- and high-sensitive blasts, low-sensitive cells showed higher levels of transcription of ATRA-target genes, transcriptional regulators, chromatin remodelers, and transcription factors. In opposition, only high-sensitive blasts expressed the CYP26A1 gene, encoding the p450 cytochrome which is known to be involved in retinoic acid catabolism. In NB4 cells, ATRA treatment activates a novel signaling pathway, whereby interleukin-8 stimulates the expression of the homeobox transcription factor HOXA10v2, an effective enhancer of CYP26A1 transcription. These data were corroborated in primary APL cells, as maturation levels correlated with CYP26A1 expression. Treatment with a retinoic acid metabolism blocking agent (RAMBA) results in high-nucleoplasmic concentrations of retinoid and growth of NB4-resistant subclones. Hence, for APL blasts associated with poor prognosis, the low CYP26A1 expression may explain high risk of resistance installation, by increased retinoid pressure. Pharmacogenomic profiles of genes involved in retinoid acid metabolism may help to optimize anticancer therapies, including retinoids.
Ronan Quere; Aurelie Baudet; Bruno Cassinat; Gerald Bertrand; Jacques Marti; Laurent Manchon; David Piquemal; Christine Chomienne; Therese Commes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-01-11
Journal Detail:
Title:  Blood     Volume:  109     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-05-07     Completed Date:  2007-07-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4450-60     Citation Subset:  AIM; IM    
Groupe d'Etude des Transcriptomes, Institut de génétique humaine, Unité Propre de Recherche, Centre National de la Recherche Scientifique, Montpellier, France.
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MeSH Terms
Cell Proliferation / drug effects
Cytochrome P-450 Enzyme System / metabolism*
Disease Progression
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / genetics
Gene Expression Profiling
Gene Expression Regulation, Leukemic / drug effects
Gene Library
Homeodomain Proteins / genetics
Interleukin-8 / metabolism
Leukemia, Promyelocytic, Acute / drug therapy*,  genetics*,  metabolism,  pathology
Models, Biological
Transcription, Genetic / drug effects
Tretinoin / metabolism,  therapeutic use*
Tumor Cells, Cultured
Reg. No./Substance:
0/Homeodomain Proteins; 0/IL8 protein, human; 0/Interleukin-8; 140441-81-2/HOXA10 protein, human; 302-79-4/Tretinoin; 9035-51-2/Cytochrome P-450 Enzyme System; EC acid 4-hydroxylase

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

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