title: 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.forename: Coralie
authors.initials: C
authors.lastname: Hoareau-Aveilla
authors.forename: Thibaud
authors.initials: T
authors.lastname: Valentin
authors.forename: Camille
authors.initials: C
authors.lastname: Daugrois
authors.forename: Cathy
authors.initials: C
authors.lastname: Quelen
authors.forename: Géraldine
authors.initials: G
authors.lastname: Mitou
authors.forename: Samuel
authors.initials: S
authors.lastname: Quentin
authors.forename: Jinsong
authors.initials: J
authors.lastname: Jia
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spicuglia
authors.forename: Pierre
authors.initials: P
authors.lastname: Ferrier
authors.forename: Monica
authors.initials: M
authors.lastname: Ceccon
authors.forename: Sylvie
authors.initials: S
authors.lastname: Giuriato
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.forename: Pierre
authors.initials: P
authors.lastname: Brousset
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamant
authors.forename: Fabienne
authors.initials: F
authors.lastname: Meggetto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000077547:Crizotinib; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000077547:Crizotinib; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D035683:MicroRNAs; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles; D011725:Pyridines; D012334:RNA, Neoplasm; D050796:STAT3 Transcription Factor; C533097:MIR150, human; C494086:STAT3 protein, human; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C107023:p80(NPM-ALK) protein