Determination of genes and microRNAs involved in the resistance to fludarabine in vivo in chronic lymphocytic leukemia

Molecular Cancer

Research

Fernand Ries¹  Caroline Duhem¹  Alain Delmer²  Pascale Cornillet-Lefebvre²  Hélène A Poirel³  Kris Van Moer⁴  Eric van Dyck⁴  Nasséra Aouali⁴  Victoria El Khoury⁴  Valérie Palissot⁴  Bernadette Leners⁴  Etienne Moussay⁴  Guy Berchem⁵  François Bernardin⁶  Laurent Vallar⁶  Arnaud Muller⁶  Thomas Wenner⁷ 

[1] Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg;Hematology Department, University Hospital, Reims, France;Human Molecular Genetics, Cliniques universitaires saint-Luc/de Duve Institute/Université Catholique de Louvain, Brussels, Belgium;Laboratory of Experimental Hemato-Oncology, CRP-Santé, Luxembourg, Luxembourg;Laboratory of Experimental Hemato-Oncology, CRP-Santé, Luxembourg, Luxembourg;Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg;Microarray Center, CRP-Santé, Luxembourg, Luxembourg;Société pour la Recherche contre le Cancer et les Maladies du Sang, Luxembourg, Luxembourg;

关键词: Chronic Lymphocytic Leukemia;    Fludarabine;    Chronic Lymphocytic Leukemia Patient;    Chronic Lymphocytic Leukemia Cell;    Sensitive Patient;   

DOI  :  10.1186/1476-4598-9-115

 received in 2009-09-09, accepted in 2010-05-20,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundChronic 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.ResultsIn 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.ConclusionIn 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.

【 授权许可】

CC BY   
© Moussay et al; licensee BioMed Central Ltd. 2010