|
|
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.
 Previous Article | Next Article 
Submitted October 10, 2006
Accepted January 5, 2007
Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity
Ronan Quere, Aurelie Baudet, Bruno Cassinat, Gerald Bertrand, Jacques Marti, Laurent Manchon, David Piquemal, Christine Chomienne, and Therese Commes*
Groupe d'Etude des Transcriptomes, Institut de Genetique Humaine, Montpellier, France
Inserm UMR-S-718, Unite de Biologie Cellulaire, Institut Universitaire d'Hematologie, Hopital Saint Louis, Paris, France
Etablissement Francais du Sang Pyrenees-Mediterranee, Laboratoire des Agents Transmissibles par Transfusion, Montpellier, France
Skuld Tech, Universite Montpellier II, Montpellier, France
* Corresponding author; email: commes{at}univ-montp2.fr.
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. In order to identify biological networks involved in resistance, we conducted pharmacogenomic studies in APL blasts displaying distinct ATRA sensitivities. While 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 to poor prognosis, the low CYP26A1 expression may explain high risk of resistance installation, by increase retinoid pressure. Pharmacogenomic profiles of genes involved in retinoid acid metabolism may help to optimize anti-cancer therapies including retinoids.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. Tabata, R. Tabata, N. Hirayama, A. Yasumitsu, S. Yamada, A. Murakami, S. Iida, K. Tamura, T. Terada, K. Kuribayashi, et al.
All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice
Eur. Respir. J.,
November 1, 2009;
34(5):
1159 - 1167.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Saumet, G. Vetter, M. Bouttier, E. Portales-Casamar, W. W. Wasserman, T. Maurin, B. Mari, P. Barbry, L. Vallar, E. Friederich, et al.
Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia
Blood,
January 8, 2009;
113(2):
412 - 421.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
