Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth
Coralie Hoareau-Aveilla, … , Laurence Lamant, Fabienne Meggetto
Coralie Hoareau-Aveilla, … , Laurence Lamant, Fabienne Meggetto
Published August 10, 2015
Citation Information: J Clin Invest. 2015;125(9):3505-3518. https://doi.org/10.1172/JCI78488.
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Research Article Oncology

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

Abstract

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.

Authors

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

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Figure 8

Schematic model of the NPM-ALK/STAT3/DNMT1/miR-150/MYB regulatory circuit in NPM-ALK(+)-associated lymphomas.

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Schematic model of the NPM-ALK/STAT3/DNMT1/miR-150/MYB regulatory circui...
In naive/sensitive cells and cells resistant to crizotinib (an ALK TKI), the NPM-ALK fusion protein inhibits the expression of miR-150 through a DNA methylation mechanism that is dependent on the STAT3 and DNMT1 proteins. In naive/crizotinib-sensitive NPM-ALK(+) cells, crizotinib or demethylating drugs such as decitabine repress the STAT3/DNMT1 axis, thus releasing miR-150 inhibition and reducing the level of its target gene, MYB. These changes, in turn, result in decreased cell proliferation and lead to lymphoma growth inhibition. Concomitantly to its large antiproliferative effect, miR-150 expression also attenuates MYB expression in crizotinib-resistant NPM-ALK(+) cells harboring a substitution mutation within the ALK KD. These findings should promote further investigation into the effect of epigenetic modulation in other ALK-related malignancies harboring either different mutation types, different ALK fusions, or overexpressed/activated ALK full-length oncogenes. Illustration created by Servier Medical Art (http://www.servier.fr/servier-medical-art).