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Blood, 16 April 2009, Vol. 113, No. 16, pp. 3801-3808.
Prepublished online as a Blood First Edition Paper on October 21, 2008; DOI 10.1182/blood-2008-08-172254.
 Previous Article | Next Article 
Submitted August 13, 2008
Accepted September 28, 2008
MiR-34a as part of the chemotherapy resistance network in chronic lymphocytic leukemia
Thorsten Zenz, Julia Mohr, Eric Eldering, Arnon P Kater, Andreas Buhler, Dirk Kienle, Dirk Winkler, Jan Durig, Marinus H.J. van Oers, Daniel Mertens, Hartmut Dohner, and Stephan Stilgenbauer*
Department of Internal Medicine III, University of Ulm, Ulm, Germany
Laboratory of Experimental Immunology, Academical Medical Center, Amsterdam, Netherlands
Department of Hematology, Academic Medical Center, Amsterdam, Netherlands
Department of Hematology, University of Duisburg-Essen, Essen, Germany
* Corresponding author; email: stephan.stilgenbauer{at}uniklinik-ulm.de.
17p (TP53) deletion identifies patients with CLL who are resistant to chemotherapy. The members of the miR-34 family have been discovered to be direct p53 targets and mediate some of the p53 dependent effects. We studied miR-34a and miR-34b/c expression in a large cohort to define their potential role in refractory CLL. While no expression of miR-34b/c could be detected, we found variable expression levels of miR-34a. miR-34a levels were up-regulated after DNA damage in the presence of functional p53 but not in cases with 17p deletion (p<0.0001). We found a strong correlation of low miR-34a levels with impaired DNA damage response, TP53 mutations (without 17p deletion) and fludarabine-refractory disease (also in the absence of 17p deletion). Up-regulation of miR-34a after irradiation was associated with induction of Bax and p21 but not Puma. CLL cells with reduced miR-34a expression showed increased viability after DNA damage independently of 17p status. Therefore, low expression of miR-34a in CLL is associated with p53 inactivation but also chemotherapy-refractory disease, impaired DNA damage response and apoptosis irrespective of 17p deletion / TP53 mutation. The elucidation of mechanisms underlying miR-34a regulation and overcoming its role in chemotherapy resistance warrant further study.
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