Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth
2015
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 methyltransferase1 (
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
decitabineor 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
crizotiniband other anti-ALK tyrosine kinase inhibitors (TKIs). Moreover, these results support further work on
miR-150 in these and other ALK(+) malignancies.
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