Journal Article

Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth

Ceccon, Monica, Hoareau-Aveilla, Coralie, Giuriato, Sylvie, Brousset, Pierre, Spicuglia, Salvatore, Meggetto, Fabienne, Ferrier, Pierre, Jia, Jinsong, Valentin, Thibaud, Mitou, Géraldine, Daugrois, Camille, Quelen, Cathy, Gambacorti-Passerini, Carlo, Lamant, Laurence, Quentin, Samuel

2015

Overview

The regulatory microRNA miR-150 is involved in the development of hemopathies and is downregulated in T-lymphomas, such as anaplastic large-cell lymphoma (ALCL) tumors. ALCL is defined by the presence or absence of translocations that activate the anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common. Here, we compared samples of primary NPM-ALK(+) and NPM-ALK(-) ALCL to investigate the role of miR-150 downstream of NPM-ALK. Methylation of the MIR150 gene was substantially elevated in NPM-ALK(+) biopsies and correlated with reduced miR-150 expression. In NPM-ALK(+) cell lines, DNA hypermethylation-mediated miR-150 repression required ALK-dependent pathways, as ALK inhibition restored miR-150 expression. Moreover, epigenetic silencing of miR-150 was due to the activation of STAT3, a major downstream substrate of NPM-ALK, in cooperation with DNA methyltransferase 1 (DNMT1). Accordingly, miR-150 repression was turned off following treatment with the DNMT inhibitor, decitabine. In murine NPM-ALK(+) xenograft models, miR-150 upregulation induced antineoplastic activity. Treatment of crizotinib-resistant NPM-ALK(+) KARPAS-299-CR06 cells with decitabine or ectopic miR-150 expression reduced viability and growth. Altogether, our results suggest that hypomethylating drugs, alone or in combination with other agents, may benefit ALK(+) patients harboring tumors resistant to crizotinib and other anti-ALK tyrosine kinase inhibitors (TKIs). Moreover, these results support further work on miR-150 in these and other ALK(+) malignancies.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Biomedical research / Cancer / Cancer therapies / Cell Line, Tumor / Chemotherapy / Comparative analysis / Crizotinib / Deoxyribonucleic acid / Disadvantages / Disease / DNA / DNA (Cytosine-5-)-Methyltransferase 1 / DNA (Cytosine-5-)-Methyltransferases - genetics / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA methylation / Drug Resistance, Neoplasm / Epigenetics / Female / Gene expression / Gene Expression Regulation, Neoplastic / Gene Silencing / Genetic aspects / Growth / Health aspects / Humans / Kinases / Life Sciences / Lymphoma / Lymphoma, Large-Cell, Anaplastic - drug therapy / Lymphoma, Large-Cell, Anaplastic - genetics / Lymphoma, Large-Cell, Anaplastic - metabolism / Lymphoma, Large-Cell, Anaplastic - pathology / Male / Medical prognosis / Mice / Mice, Transgenic / MicroRNA / MicroRNAs / MicroRNAs - biosynthesis / MicroRNAs - genetics / Mutation / Non-Hodgkin's lymphomas / Protein-Tyrosine Kinases - genetics / Protein-Tyrosine Kinases - metabolism / Pyrazoles - pharmacology / Pyridines - pharmacology / Risk factors / RNA, Neoplasm - biosynthesis / RNA, Neoplasm - genetics / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Tumors