Abstract
BackgroundFludarabine, is one of the most active single agents in the treatment of chronic lymphocytic leukemia (CLL). Over time, however, virtually all CLL patients become fludarabine-refractory. To elucidate whether microRNAs are involved in the development of fludarabine resistance, we analyzed the expression of 723 human miRNAs before and 5-days after fludarabine mono-therapy in 17 CLL patients which were classified as responder or refractory to fludarabine treatment based on NCI criteria.ResultsBy comparing the expression profiles of these two groups of patients, we identified a microRNA signature able to distinguish refractory from sensitive CLLs. The expression of some microRNAs was also able to predict fludarabine resistance of 12 independent CLL patients. Among the identified microRNAs, miR-148a, miR-222 and miR-21 exhibited a significantly higher expression in non-responder patients either before and after fludarabine treatment. After performing messenger RNA expression profile of the same patients, the activation of p53-responsive genes was detected in fludarabine responsive cases only, therefore suggesting a possible mechanism linked to microRNA deregulation in non-responder patients. Importantly, inhibition of miR-21 and miR-222 by anti-miRNA oligonucleotides induced a significant increase in caspase activity in fludarabine-treated p53-mutant MEG-01 cells, suggesting that miR-21 and miR-222 up-regulation may be involved in the establishment of fludarabine resistance.ConclusionsThis is the first report that reveals the existence of a microRNA profile that differentiate refractory and sensitive CLLs, either before and after fludarabine mono-therapy. A p53 dysfunctional pathway emerged in refractory CLLs and could contribute in explaining the observed miRNA profile. Moreover, this work indicates that specific microRNAs can be used to predict fludarabine resistance and may potentially be used as therapeutic targets, therefore establishing an important starting point for future studies.
Highlights
Fludarabine, is one of the most active single agents in the treatment of chronic lymphocytic leukemia (CLL)
Based on NCI criteria, 9 of the patients exhibited a clinical response (CR), i.e. they attained either complete or partial response, while 8 patients were resistant to the treatment and were classified as non responders (NR)
Fludarabine induces a modulation of miRNA expression that exhibits a differential expression between responder and non-responder patients We evaluated the miRNAs expression in 33 samples obtained from CLL patients before and after treatment, hereafter called pre and post, through the hybridization on a miRNA platform (Agilent technologies) able to assess the expression levels of 723 human miRNAs (MiRBASE release 10.1)
Summary
Fludarabine, is one of the most active single agents in the treatment of chronic lymphocytic leukemia (CLL). To elucidate whether microRNAs are involved in the development of fludarabine resistance, we analyzed the expression of 723 human miRNAs before and 5-days after fludarabine mono-therapy in 17 CLL patients which were classified as responder or refractory to fludarabine treatment based on NCI criteria. A significant fraction of patients do not respond or become resistant to MicroRNAs (miRNAs) have been involved in the regulation of many physiological and pathological processes, through their wide action as post-transcriptional gene expression modulators [8,9]. MiR-29c and miR-223 have been used to create a quantitative PCR-based score able to improve CLL patients stratification in terms of treatment free survival and overall survival, when combined with two other prognostic factors [18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
