STAT3-mediated activation of microRNA cluster 17~92 promotes proliferation and survival of ALK-positive anaplastic large cell lymphoma

Elisa Spaccarotella, Elisa Pellegrino, Manuela Ferracin, Cristina Ferreri, Giuditta Cuccuru, Cuiling Liu, Javeed Iqbal, Daniela Cantarella, Riccardo Taulli, Paolo Provero, Ferdinando Di Cunto, Enzo Medico, Massimo Negrini, Wing C. Chan, Giorgio Inghirami, Roberto Piva

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Systemic anaplastic large cell lymphoma is a category of T-cell non-Hodgkin's lymphoma which can be further subdivided into two distinct entities (ALK+ and ALK-) based on the presence or absence of ALK gene rearrangements. Among several pathways triggered by ALK signaling, constitutive activation of STAT3 is strictly required for ALK-mediated transformation and survival. Here we performed genome-wide microRNA profiling and identified 48 microRNA concordantly modulated by the inducible knock-down of ALK and STAT3. To evaluate the functional role of differentially expressed miRNA, we forced their expression in ALK+ anaplastic large cell lymphoma cells, and monitored their influence after STAT3 depletion. We found that the expression of the microRNA-17~92 cluster partially rescues STAT3 knock-down by sustaining proliferation and survival of ALK+ cells. Experiments in a xenograft mouse model indicated that forced expression of microRNA-17~92 interferes with STAT3 knock-down in vivo. High expression levels of the microRNA-17~92 cluster resulted in down-regulation of BIM and TGFβRII proteins, suggesting that their targeting might mediate resistance to STAT3 knock-down in anaplastic large cell lymphoma cells. We speculate that the microRNA-17~92 cluster is involved in lymphomagenesis of STAT3+ ALCL and that its inhibition might represent an alternative avenue to interfere with ALK signaling in anaplastic large cell lymphomas.

Original languageEnglish (US)
Pages (from-to)116-124
Number of pages9
JournalHaematologica
Volume99
Issue number1
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Hematology

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