Abstract
Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.
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Acknowledgements
In addition to the authors listed, the following investigators participated in this study as part of the GISL—Gruppo Italiano Studio Linfomi: Gianni Quintana, Divisione di Ematologia, Presidio Ospedaliero ‘A. Perrino’, Brindisi; Giovanni Bertoldero, Dipartimento di Oncologia, Ospedale Civile, Noale, Venezia; Paolo Di Tonno, Dipartimento di Ematologia, Venere, Bari; Robin Foà and Francesca R Mauro, Divisione di Ematologia, Università La Sapienza, Roma; Nicola Di Renzo, Unità di Ematologia, Ospedale Vito Fazzi, Lecce; Maria Cristina Cox, Ematologia, A.O. Sant’Andrea, Università La Sapienza, Roma; Stefano Molica, Dipartimento di Oncologia ed Ematologia, Pugliese-Ciaccio Hospital, Catanzaro; Attilio Guarini, Unità di Ematologia e Trapianto di Cellule Staminali, Istituto di Oncologia ‘Giovanni Paolo II’, Bari; Antonio Abbadessa, U.O.C. di Oncoematologia Ospedale ‘S. Anna e S. Sebastiano’, Caserta; Francesco Iuliano, U.O.C. di Oncologia, Ospedale Giannettasio, Rossano Calabro, Cosenza; Omar Racchi, Ospedale Villa Scassi Sampierdarena, Genova; Mauro Spriano, Ematologia, A.O. San Martino, Genova; Felicetto Ferrara, Divisione di Ematologia, Ospedale Cardarelli, Napoli; Monica Crugnola, Ematologia, CTMO, Azienda Ospedaliera Universitaria di Parma; Alessandro Andriani, Dipartimento di Ematologia, Ospedale Nuovo Regina Margherita, Roma; Nicola Cascavilla, Unità di Ematologia e Trapianto di Cellule Staminali, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo; Lucia Ciuffreda, Unità di Ematologia, Ospedale San Nicola Pellegrino, Trani; Graziella Pinotti, U.O. Oncologia Medica, Ospedale di Circolo Fondazione Macchi, Varese; Anna Pascarella, Unità Operativa di Ematologia, Ospedale dell'Angelo, Venezia-Mestre; Maria Grazia Lipari, Divisione di Ematologia, Ospedale Policlinico, Palermo, Francesco Merli, Unità Operativa di Ematologia, A.O.S. Maria Nuova, Reggio Emilia; Luca Baldini Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda-Maggiore Policlinico, Milano; Caterina Musolino, Divisione di Ematologia, Università di Messina; Agostino Cortelezzi, Ematologia and CTMO, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano; Francesco Angrilli, Dipartimento di Ematologia, Ospedale Santo Spirito, Pescara; Ugo Consoli, U.O.S. di Emato-Oncologia, Ospedale Garibaldi-Nesima, Catania; Gianluca Festini, Centro di Riferimento Ematologico-Seconda Medicina, Azienda Ospedaliero-Universitaria, Ospedali Riuniti, Trieste; Giuseppe Longo, Unità di Ematologia, Ospedale San Vincenzo, Taormina; Daniele Vallisa and Annalisa Arcari, Unità di Ematologia, Dipartimento di Onco-Ematologia, Guglielmo da Saliceto Hospital, Piacenza; Francesco Di Raimondo and Annalisa Chiarenza, Divisione di Ematologia, Università di Catania Ospedale Ferrarotto, Catania; Iolanda Vincelli, Unità di Ematologia, A.O. of Reggio Calabria; Donato Mannina, Divisione di Ematologia, Ospedale Papardo, Messina, Italy. This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC) Grant 5 x mille n.9980, (to MF, FM, AN, PT and MN); AIRC I.G. n.14326 (to MF), n.10136 and 16722 (AN), n.15426 (to FF). AIRC and Fondazione CaRiCal co-financed Multi Unit Regional Grant 2014 n.16695 (to FM). Italian Ministry of Health 5x1000 funds (to SZ and FF). AGR was supported by Associazione Italiana contro le Leucemie-Linfomi-Mielomi (AIL) Cosenza—Fondazione Amelia Scorza (FAS). SM, CM, MC, LE and SB were supported by AIRC.
Author contributions
Conception and design: GC, GB, FF and MF; Development of methodology: GC, SM, CM, GB, MC, DR, RM, SS, SB, LE and SF; Acquisition of data: GC, SM, LE, MC, GB, MM, SF, SS, DR, RM, FV, SZ, FM and MN; Analysis and interpretation of data: GC, SM, GB, CM, AN, SS, MC, SF, CEN, MC, FR, LB, FF, SZ, MN, PT, MG, MT, MF and FM; Writing, review, and/or revision of the manuscript: GC, AGR, MN, PT, AN, FF and MF; Study supervision: GC, FF and MF. All authors reviewed and approved the manuscript.
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Cutrona, G., Matis, S., Colombo, M. et al. Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy. Leukemia 31, 1894–1904 (2017). https://doi.org/10.1038/leu.2016.394
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DOI: https://doi.org/10.1038/leu.2016.394
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