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

J Clin Invest. 2015 Sep;125(9):3505-18. doi: 10.1172/JCI78488. Epub 2015 Aug 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Crizotinib
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing*
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / drug therapy
  • Lymphoma, Large-Cell, Anaplastic / genetics
  • Lymphoma, Large-Cell, Anaplastic / metabolism*
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • RNA, Neoplasm / biosynthesis*
  • RNA, Neoplasm / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism


  • MIRN150 microRNA, human
  • MicroRNAs
  • Pyrazoles
  • Pyridines
  • RNA, Neoplasm
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Crizotinib
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Dnmt1 protein, mouse
  • p80(NPM-ALK) protein
  • Protein-Tyrosine Kinases