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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. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: blood-2008-08-172254v1 113/16/3801    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zenz, T. Articles by Stilgenbauer, S. Search for Related Content PubMed PubMed Citation Articles by Zenz, T. Articles by Stilgenbauer, S. Related Collections Lymphoid Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA miR-34a as part of the resistance network in chronic lymphocytic leukemia Thorsten Zenz1, Julia Mohr1, Eric Eldering2, Arnon P. Kater3, Andreas Bühler1, Dirk Kienle1, Dirk Winkler1, Jan Dürig4, Marinus H. J. van Oers3, Daniel Mertens1, Hartmut Döhner1, and Stephan Stilgenbauer1 1 Department of Internal Medicine III, University of Ulm, Ulm, Germany; 2 Laboratory of Experimental Immunology and 3 Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands; and 4 Department of Hematology, University of Duisburg-Essen, Essen, Germany 17p (TP53) deletion identifies patients with chronic lymphocytic leukemia (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 < .001). 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 resistance irrespective of 17p deletion/TP53 mutation. The elucidation of mechanisms underlying miR-34a regulation and overcoming its role in chemotherapy resistance warrant further study. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: MiR-sensing chemotherapy resistance in CLL George A. Calin Blood 2009 113: 3652-3653. [Full Text] [PDF] This article has been cited by other articles: R. Visone, L. Z. Rassenti, A. Veronese, C. Taccioli, S. Costinean, B. D. Aguda, S. Volinia, M. Ferracin, J. Palatini, V. Balatti, et al. Karyotype-specific microRNA signature in chronic lymphocytic leukemia Blood, October 29, 2009; 114(18): 3872 - 3879. [Abstract] [Full Text] [PDF] C. P. Pallasch, M. Patz, Y. J. Park, S. Hagist, D. Eggle, R. Claus, S. Debey-Pascher, A. Schulz, L. P. Frenzel, J. Claasen, et al. miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia Blood, October 8, 2009; 114(15): 3255 - 3264. [Abstract] [Full Text] [PDF] T. Zenz, S. Habe, T. Denzel, J. Mohr, D. Winkler, A. Buhler, A. Sarno, S. Groner, D. Mertens, R. Busch, et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial Blood, September 24, 2009; 114(13): 2589 - 2597. [Abstract] [Full Text] [PDF] P. R. di Val Cervo, P. Tucci, A. Majid, M. A. Lena, M. Agostini, S. Bernardini, E. Candi, G. Cohen, P. Nicotera, M. J. S. Dyer, et al. p73, miR106b, miR34a, and Itch in chronic lymphocytic leukemia Blood, June 18, 2009; 113(25): 6498 - 6499. [Full Text] [PDF] D. Sampath and W. Plunkett Response: Context-dependent actions of miR-106b in CLL Blood, June 18, 2009; 113(25): 6499 - 6500. [Full Text] [PDF] D. Sampath and G. A. Calin miRs: fine-tuning prognosis in CLL Blood, May 21, 2009; 113(21): 5035 - 5036. [Full Text] [PDF] Chemotherapy Resistance in Chronic Lymphocytic Leukemia Journal Watch Oncology and Hematology, May 19, 2009; 2009(519): 4 - 4. [Full Text] G. A. Calin MiR-sensing chemotherapy resistance in CLL Blood, April 16, 2009; 113(16): 3652 - 3653. [Full Text] [PDF]

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