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.