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Chronic Lymphocytic Leukemia

The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes

Leukemia volume 26, pages 1584–1593 (2012)Cite this article

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Abstract

Chronic lymphocytic leukemia (CLL) cells from clinically aggressive cases have a greater capacity to respond to external microenvironmental stimuli, including those transduced through Toll-like-receptor-9 (TLR9). Concomitant microRNA and gene expression profiling in purified CLL cells (n=17) expressing either unmutated (UM) or mutated (M) IGHV genes selected microRNAs from the miR-17∼92 family as significantly upregulated and in part responsible for modifications in the gene expression profile of UM CLL cells stimulated with the TLR9 agonist CpG. Notably, the stable and sustained upregulation of miR-17∼92 microRNAs by CpG was preceded by a transient induction of the proto-oncogene MYC. The enforced expression of miR-17, a major member from this family, reduced the expression of the tumor suppressor genes E2F5, TP53INP1, TRIM8 and ZBTB4, and protected cells from serum-free-induced apoptosis (P⩽0.05). Consistently, transfection with miR-17∼92 family antagomiRs reduced Bromo-deoxy-uridine incorporation in CpG-stimulated UM CLL cells. Finally, miR-17 expression levels, evaluated in 83 CLL samples, were significantly higher in UM (P=0.03) and ZAP-70high (P=0.02) cases. Altogether, these data reveal a role for microRNAs of the miR-17∼92 family in regulating pro-survival and growth-promoting responses of CLL cells to TLR9 triggering. Overall, targeting of this pathway may represent a novel therapeutic option for management of aggressive CLL.

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Acknowledgements

This work was 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-2009-1475467, Rome, Italy; Progetto Giovani Ricercatori n. GR-2008-1138053, 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, Investigator Grant IG-8701, IG-5917 and MFAG-10327), Milan, Italy; ‘5 × 1000 Intramural Program’, Centro di Riferimento Oncologico, Aviano, Italy; and The Leukemia & Lymphoma Society (grant no. R6170-10), White Plains, NY.

Author contributions

RB performed the research and wrote the manuscript; SG and MDB performed the research and contributed to the writing of the manuscript; ET, AZ and DB performed the research; SV and DM analyzed the miRNA and gene expression data; DR, GDP, GG and LL provided patients’ data; and DGE and VG designed the study and wrote the manuscript.

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Author notes

  1. D G Efremov and V Gattei: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, PN, Italy

    R Bomben, M Dal Bo, D Marconi, E Tissino, D Benedetti, A Zucchetto & V Gattei

  2. Department of Molecular Hematology, ICGEB Outstation-Monterotondo, Rome, Italy

    S Gobessi & D G Efremov

  3. Department of Morphology and Embryology, DAMA, Data Mining for Analysis of Microarrays, University of Ferrara, Ferrara, Italy

    S Volinia

  4. Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA

    S Volinia

  5. Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    S Volinia

  6. Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    D Rossi & G Gaidano

  7. Division of Hematology, S.Eugenio Hospital and University of Tor Vergata, Rome, Italy

    G Del Poeta

  8. Department of Hematology, Catholic University Hospital A. Gemelli, Rome, Italy

    L Laurenti

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Bomben, R., Gobessi, S., Dal Bo, M. et al. The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes. Leukemia 26, 1584–1593 (2012). https://doi.org/10.1038/leu.2012.44

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