- Letter to the Editor
- Open Access
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.
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