MicroRNAs involvement in fludarabine refractory chronic lymphocytic leukemia

Molecular Cancer

Research

Barbara Zagatti¹  Massimo Negrini¹  Angelo Veronese¹  Laura Lupini¹  Andrea Grilli¹  Manuela Ferracin¹  Elena Saccenti²  Francesco Cavazzini³  Antonio Cuneo³  Maria Ciccone³  Lara Rizzotto³  Cristiano De Angeli³ 

[1] Dipartimento di Medicina Sperimentale e Diagnostica Università di Ferrara, Ferrara, Italy;Dipartimento di Medicina Sperimentale e Diagnostica Università di Ferrara, Ferrara, Italy;Dipartimento di Scienze Biomediche e Terapie Avanzate, Università di Ferrara, Ferrara, Italy;Dipartimento di Scienze Biomediche e Terapie Avanzate, Università di Ferrara, Ferrara, Italy;

关键词: Chronic Lymphocytic Leukemia;    miRNA Expression;    Fludarabine;    Bendamustine;    Chronic Lymphocytic Leukemia Patient;   

DOI  :  10.1186/1476-4598-9-123

 received in 2009-10-15, accepted in 2010-05-26,  发布年份 2010

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Ferracin et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.