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Doxorubicin-induced loss of DNA topoisomerase II and DNMT1- dependent suppression of MiR-125b induces chemoresistance in ALK-positive cells.
Congras, Annabelle; Caillet, Nina; Torossian, Nouritza; Quelen, Cathy; Daugrois, Camille; Brousset, Pierre; Lamant, Laurence; Meggetto, Fabienne; Hoareau-Aveilla, Coralie.
Afiliación
  • Congras A; Inserm, UMR1037 CRCT, F-31000 Toulouse, France.
  • Caillet N; Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.
  • Torossian N; CNRS, ERL5294 CRCT, F-31000 Toulouse, France.
  • Quelen C; Equipe Labelisée LIGUE 2017.
  • Daugrois C; Inserm, UMR1037 CRCT, F-31000 Toulouse, France.
  • Brousset P; Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.
  • Lamant L; CNRS, ERL5294 CRCT, F-31000 Toulouse, France.
  • Meggetto F; Equipe Labelisée LIGUE 2017.
  • Hoareau-Aveilla C; Inserm, UMR1037 CRCT, F-31000 Toulouse, France.
Oncotarget ; 9(18): 14539-14551, 2018 Mar 06.
Article en En | MEDLINE | ID: mdl-29581862
Systemic anaplastic large-cell lymphoma (ALCL) is a childhood T cell neoplasm defined by the presence or absence of translocations that lead to the ectopic expression of anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common. Polychemotherapy involving doxorubicin is the standard first-line treatment but for the 25 to 35% of patients who relapse and develop resistance the prognosis remains poor. We studied the potential role of the microRNA miR-125b in the development of resistance to doxorubicin in NPM-ALK(+) ALCL. Our results show that miR-125b expression is repressed in NPM-ALK(+) cell lines and patient samples through hypermethylation of its promoter. NPM-ALK activity, in cooperation with DNA topoisomerase II (Topo II) and DNA methyltransferase 1 (DNMT1), is responsible for miR-125b repression through DNA hypermethylation. MiR-125b repression was reversed by the inhibition of DNMTs with decitabine or the inhibition of DNA topoisomerase II with either doxorubicin or etoposide. In NPM-ALK(+) cell lines, doxorubicin treatment led to an increase in miR-125b levels by inhibiting the binding of DNMT1 to the MIR125B1 promoter and downregulating the pro-apoptotic miR-125b target BAK1. Reversal of miR-125b silencing, increased miR-125b levels and reduced BAK1 expression also led to a lower efficacy of doxorubicin, suggestive of a pharmacoresistance mechanism. In line with this, miR-125b repression and increased BAK1 expression correlated with early relapse in human NPM-ALK(+) ALCL primary biopsies. Collectively our findings suggest that miR-125b could be used to predict therapeutic outcome in NPM-ALK(+) ALCL.
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Texto completo: 1 Bases de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Oncotarget Año: 2018 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Bases de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Oncotarget Año: 2018 Tipo del documento: Article País de afiliación: Francia