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Leukemia. 2017 Sep;31(9):1894-1904. doi: 10.1038/leu.2016.394. Epub 2017 Jan 5.

Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy.

Author information

1
Department Integrated Oncological Therapies, Molecular Pathology Unit, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
2
Diagnostic Imaging and Senology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
3
Department of Experimental Medicine, University of Genova, Genoa, Italy.
4
Animal Facility, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
5
Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
6
Hematology Unit, Department of Onco-Hematology, A.O. of Cosenza, Cosenza, Italy.
7
Biotechnology Research Unit, Aprigliano, A.O./ASP of Cosenza, Cosenza, Italy.
8
Division of Histopathology and Cytopathology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
9
Department of Science of Health (DISSAL), University of Genoa, Genoa, Italy.
10
Molecular Diagnostic Unit, Division of Histopathology and Cytopathology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
11
Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
12
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
13
Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy.
14
Scientific Direction, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.

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,╬│cnull (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.

PMID:
28053325
DOI:
10.1038/leu.2016.394
[Indexed for MEDLINE]

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