Research Papers:

Doxorubicin-induced loss of DNA topoisomerase II and DNMT1- dependent suppression of MiR-125b induces chemoresistance in ALK-positive cells

Annabelle Congras _, Nina Caillet, Nouritza Torossian, Cathy Quelen, Camille Daugrois, Pierre Brousset, Laurence Lamant, Fabienne Meggetto and Coralie Hoareau-Aveilla

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Oncotarget. 2018; 9:14539-14551. https://doi.org/10.18632/oncotarget.24465

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Annabelle Congras1,2,3,7,*, Nina Caillet1,2,3,7,*, Nouritza Torossian1,2,3, Cathy Quelen1,2,3,7, Camille Daugrois1,2,3, Pierre Brousset1,2,3,4,5,6,7, Laurence Lamant1,2,3,4,5,6,7, Fabienne Meggetto1,2,3,4,5,6,7 and Coralie Hoareau-Aveilla1,2,3,7

1Inserm, UMR1037 CRCT, F-31000 Toulouse, France

2Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France

3CNRS, ERL5294 CRCT, F-31000 Toulouse, France

4Institut Carnot Lymphome-CALYM, 31024, Toulouse, France

5Laboratoire d’Excellence Toulouse Cancer-TOUCAN, 31024, Toulouse, France

6European Research Initiative on ALK-related malignancies (ERIA) (http://www.erialcl.net/)

7Equipe Labelisée LIGUE 2017

*Co–first authors

Correspondence to:

Fabienne Meggetto, email: [email protected]

Keywords: miR-125b; chemoresistance; doxorubicin; DNA topoisomerase II; DNMT1

Received: November 11, 2017     Accepted: November 20, 2017     Epub: February 08, 2018     Published: March 06, 2018


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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