TY - JOUR
T1 - Determination of genes and microRNAs involved in the resistance to fludarabine in vivo in chronic lymphocytic leukemia
AU - Moussay, Etienne
AU - Palissot, Valérie
AU - Vallar, Laurent
AU - Poirel, Hélène A.
AU - Wenner, Thomas
AU - El Khoury, Victoria
AU - Aouali, Nasséra
AU - Van Moer, Kris
AU - Leners, Bernadette
AU - Bernardin, François
AU - Muller, Arnaud
AU - Cornillet-Lefebvre, Pascale
AU - Delmer, Alain
AU - Duhem, Caroline
AU - Ries, Fernand
AU - van Dyck, Eric
AU - Berchem, Guy
N1 - Funding Information:
This work was supported by grants from the Télévie N° 7.4552.05 to EM and BL and N° 7.4556.05 to VEK and KVM. The authors thank Maria Pires-Pacheco and Manon Bosseler for their technical assistance and Dr Petr Nazarov and Dr Mika-laï Yatskou (Microarray Center, CRP-Sant)é for the statistical evaluation of the quality of microarrays. We are grateful to all CLL patients who donated blood for this study.
PY - 2010/5/20
Y1 - 2010/5/20
N2 - Background: Chronic lymphocytic leukemia (CLL) cells are often affected by genomic aberrations targeting key regulatory genes. Although fludarabine is the standard first line therapy to treat CLL, only few data are available about the resistance of B cells to this purine nucleoside analog in vivo. Here we sought to increase our understanding of fludarabine action and describe the mechanisms leading to resistance in vivo. We performed an analysis of genomic aberrations, gene expression profiles, and microRNAs expression in CLL blood B lymphocytes isolated during the course of patients' treatment with fludarabine.Results: In sensitive patients, the differentially expressed genes we identified were mainly involved in p53 signaling, DNA damage response, cell cycle and cell death. In resistant patients, uncommon genomic abnormalities were observed and the resistance toward fludarabine could be characterized based on the expression profiles of genes implicated in lymphocyte proliferation, DNA repair, and cell growth and survival. Of particular interest in some patients was the amplification of MYC (8q) observed both at the gene and transcript levels, together with alterations of myc-transcriptional targets, including genes and miRNAs involved in the regulation of cell cycle and proliferation. Differential expression of the sulfatase SULF2 and of miR-29a, -181a, and -221 was also observed between resistant and sensitive patients before treatment. These observations were further confirmed on a validation cohort of CLL patients treated with fludarabine in vitro.Conclusion: In the present study we identified genes and miRNAs that may predict clinical resistance of CLL to fludarabine, and describe an interesting oncogenic mechanism in CLL patients resistant to fludarabine by which the complete MYC-specific regulatory network was altered (DNA and RNA levels, and transcriptional targets). These results should prove useful for understanding and overcoming refractoriness to fludarabine and also for predicting the clinical outcome of CLL patients before or early during their treatment.
AB - Background: Chronic lymphocytic leukemia (CLL) cells are often affected by genomic aberrations targeting key regulatory genes. Although fludarabine is the standard first line therapy to treat CLL, only few data are available about the resistance of B cells to this purine nucleoside analog in vivo. Here we sought to increase our understanding of fludarabine action and describe the mechanisms leading to resistance in vivo. We performed an analysis of genomic aberrations, gene expression profiles, and microRNAs expression in CLL blood B lymphocytes isolated during the course of patients' treatment with fludarabine.Results: In sensitive patients, the differentially expressed genes we identified were mainly involved in p53 signaling, DNA damage response, cell cycle and cell death. In resistant patients, uncommon genomic abnormalities were observed and the resistance toward fludarabine could be characterized based on the expression profiles of genes implicated in lymphocyte proliferation, DNA repair, and cell growth and survival. Of particular interest in some patients was the amplification of MYC (8q) observed both at the gene and transcript levels, together with alterations of myc-transcriptional targets, including genes and miRNAs involved in the regulation of cell cycle and proliferation. Differential expression of the sulfatase SULF2 and of miR-29a, -181a, and -221 was also observed between resistant and sensitive patients before treatment. These observations were further confirmed on a validation cohort of CLL patients treated with fludarabine in vitro.Conclusion: In the present study we identified genes and miRNAs that may predict clinical resistance of CLL to fludarabine, and describe an interesting oncogenic mechanism in CLL patients resistant to fludarabine by which the complete MYC-specific regulatory network was altered (DNA and RNA levels, and transcriptional targets). These results should prove useful for understanding and overcoming refractoriness to fludarabine and also for predicting the clinical outcome of CLL patients before or early during their treatment.
UR - http://www.scopus.com/inward/record.url?scp=77952383254&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/20487546
U2 - 10.1186/1476-4598-9-115
DO - 10.1186/1476-4598-9-115
M3 - Article
C2 - 20487546
AN - SCOPUS:77952383254
SN - 1476-4598
VL - 9
JO - Molecular Cancer
JF - Molecular Cancer
M1 - 115
ER -