Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity.
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.
Quere
Ronan
R
Groupe d'Etude des Transcriptomes, Institut de génétique humaine, Unité Propre de Recherche, Centre National de la Recherche Scientifique, Montpellier, France.
Baudet
Aurelie
A
Cassinat
Bruno
B
Bertrand
Gerald
G
Marti
Jacques
J
Manchon
Laurent
L
Piquemal
David
D
Chomienne
Christine
C
Commes
Therese
T
D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D015723:Gene Library; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D010597:Pharmacogenetics; D000072516:Retinoic Acid 4-Hydroxylase; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
C508606:CXCL8 protein, human; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D016209:Interleukin-8; C069634:HOXA10 protein, human; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase