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 Blood, 15 May 2007, Vol. 109, No. 10, pp. 4450-4460.
Prepublished online as a Blood First Edition Paper on January 11, 2007; DOI 10.1182/blood-2006-10-051086.

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NEOPLASIA

Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity

Ronan Quere1, Aurelie Baudet1, Bruno Cassinat2, Gerald Bertrand3, Jacques Marti1, Laurent Manchon4, David Piquemal4, Christine Chomienne2, and Therese Commes1

1 Groupe d'Etude des Transcriptomes, Institut de génétique humaine, Unité propre de recherche (UPR) Centre National de la Recherche Scientifique (CNRS) 1142, Montpellier, France; 2 Institut National de la Santé et de la Recherche Médicale (INSERM) Unité mixte de recherche (UMR)–S-718, Unité de Biologie Cellulaire, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France; 3 Etablissement Français du Sang Pyrénées-Méditerranée, Laboratoire des Agents Transmissibles par Transfusion, Montpellier, France; 4 Skuld Tech, CC091, Université Montpellier II, Montpellier, France

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.


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