Potential therapeutic role of antagomiR17 for the treatment of chronic lymphocytic leukemia
© Dereani et al.; licensee BioMed Central Ltd. 2014
Received: 17 July 2014
Accepted: 12 October 2014
Published: 23 October 2014
Recently it was reported that microRNA from the miR-17 ~ 92 family may have a key role in chronic lymphocytic leukemia (CLL). Here, we designed specific oligonucleotides to target endogenous miR-17 (antagomiR17). In-vitro administration of antagomiR17 effectively reduced miR-17 expression and the proliferation of CLL-like MEC-1 cells. When injected in-vivo in tumor generated by the MEC-1 cells in SCID mice, antagomiR17 dramatically reduced tumor growth and significantly increase survival. Altogether, our results provide the rationale for the use of antagomiR17 as a novel potential therapeutic tool in CLL and in other lymphoproliferative disorders where miR-17 has a driver role in tumor progression.
We have recently reported that microRNA from the miR-17 ~ 92 family may be responsible for the increased proliferation/survival in chronic lymphocytic leukemia (CLL) cells expressing unmutated (UM) IGHV genes and with high level of ZAP-70 . In particular, the enforced expression of miR-17 reduced the expression of the tumor suppressor genes E2F5, TP53INP1, TRIM8 and ZBTB4, and protected CLL cells from apoptosis . Here, we provide evidences that the abrogation of miR-17 expression by a specific antagomiR is sufficient to inhibit leukemic growth and progression both in-vitro and in-vivo.
Peripheral blood samples from CLL patients were obtained in accordance with local Institutional Review Board requirements and declaration of Helsinki. CLL cell stimulation, microRNA and gene expression were performed as reported ,. MEC-1 CLL-like cell line was transfected with a molecule against miR-17 (hereafter antagomiR17), or scrambled control. In in-vivo experiments, tumors generated by MEC-1 cells into severe combined immunodeficiency (SCID) mice were treated with antagomiR17, scrambled control, or saline solution (see Additional file 1).
Evidences reported here underline that miR-17 knockdown is sufficient to block CLL-like cells proliferation both in-vitro and in-vivo. Clinically, despite recent treatment advances, some CLL seem to be refractory to the new drugs -. In this context, antagomiR treatment may represent a commendable alternative, also considering recent antagomiR phase II trials -. This strategy could be extended to other lymphoproliferative disorders where miR-17 ~ 92 amplification and/or overexpression have a pathogenetic role ,. In conclusion, our results highlight the therapeutic potential of antagomiR17, providing the rationale for its use also in the context of specific target delivering systems (e.g. nanoparticles).
SD, PM performed research, and contributed to write the manuscript; TDA, NM, MDB, SC, AZ, ET performed research and in vivo experiments; GDP provided patients data; SZ, in vivo experiments; VG, RB designed the study and wrote the manuscript. All authors read and approved the final manuscript.
Sara Dereani and Paolo Macor contributed to this study as first authors.
Valter Gattei and Riccardo Bomben equally contributed to this study as senior authors.
Supported in part by: Ministero della Salute (Ricerca Finalizzata I.R.C.C.S., “Alleanza Contro il Cancro”; Rete Nazionale Bio-Informatica Oncologica/RN-BIO; Progetto Giovani Ricercatori n. GR-2011-02347441, n. GR-2009-1475467, n. GR-2008-1138053, Ministero della Salute, Rome, Italy; Fondazione Internazionale di Ricerca in Medicina Sperimentale (FIRMS); Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore Group, Italy; Ricerca Scientifica Applicata, Regione Friuli Venezia Giulia (“Linfonet“ Project), Trieste, Italy; the Associazione Italiana Ricerca Cancro (AIRC), Grants n. IG-13227, MFAG-10327, Milan, Italy; “5x1000 Intramural Program”, Centro di Riferimento Oncologico, Aviano, Italy.
- Bomben R, Gobessi S, Dal BM, Volinia S, Marconi D, Tissino E, Benedetti D, Zucchetto A, Rossi D, Gaidano G, Del PG, Laurenti L, Efremov DG, Gattei V: The miR-17-92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes. Leukemia. 2012, 26: 1584-1593. 10.1038/leu.2012.44.View ArticlePubMedGoogle Scholar
- Bomben R, Dal-Bo M, Benedetti D, Capello D, Forconi F, Marconi D, Bertoni F, Maffei R, Laurenti L, Rossi D, Del Principe MI, Luciano F, Sozzi E, Cattarossi I, Zucchetto A, Rossi FM, Bulian P, Zucca E, Nicoloso MS, Degan M, Marasca R, Efremov DG, Del PG, Gaidano G, Gattei V: Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features. Clin Cancer Res. 2010, 16: 620-628. 10.1158/1078-0432.CCR-09-1638.View ArticlePubMedGoogle Scholar
- Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O’Brien S: Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013, 369: 32-42. 10.1056/NEJMoa1215637.PubMed CentralView ArticlePubMedGoogle Scholar
- Tiao G, Kiezun A, Wang Y, Werner L, Sougnez C, Tesar B, Fernandes SM, Vartanov AR, Hoang K, Neuberg DS, Getz G, Brown JR: NF-kB pathway mutations modulate cell survival and ibrutinib response in chronic lymphocytic leukemia. Blood. 2013, 122: 670-Google Scholar
- Landau D, Hoellenriegel J, Sougnez C, Schlesner M, Ishaque N, Brors B, Keating MJ, Wierda WG, Cibulskis K, Kantarjian HM, O’Brien SM, Neuberg DS, Zenz T, Getz G, Wu CJ: Clonal evolution in patients with chronic lymphocytic leukemia (CLL) developing resistance to BTK inhibition. Blood. 2013, 122: 866-Google Scholar
- Thorsen SB, Obad S, Jensen NF, Stenvang J, Kauppinen S: The therapeutic potential of microRNAs in cancer. Cancer J. 2012, 18: 275-284. 10.1097/PPO.0b013e318258b5d6.View ArticlePubMedGoogle Scholar
- Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges MR: Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013, 368: 1685-1694. 10.1056/NEJMoa1209026.View ArticlePubMedGoogle Scholar
- Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M: Silencing of microRNAs in vivo with `antagomirs’. Nature. 2005, 438: 685-689. 10.1038/nature04303.View ArticlePubMedGoogle Scholar
- Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, Carty S, Lam LT, Shaffer AL, Xiao W, Powell J, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Campo E, Jaffe ES, Delabie J, Smeland EB, Rimsza LM, Fisher RI, Weisenburger DD, Chan WC, Staudt LM: Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci USA. 2008, 105: 13520-13525. 10.1073/pnas.0804295105.PubMed CentralView ArticlePubMedGoogle Scholar
- Ota A, Tagawa H, Karnan S, Tsuzuki S, Karpas A, Kira S, Yoshida Y, Seto M: Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. Cancer Res. 2004, 64: 3087-3095. 10.1158/0008-5472.CAN-03-3773.View ArticlePubMedGoogle Scholar
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/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.