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

Systemic Anaplastic Large Cell Lymphoma represents a category of T-cell Non-Hodgkin Lymphoma further subdivided into two distinct entities (ALK+ and ALK-), based on the presence 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 a genome-wide miRNA profiling and identified 48 miRNAs concordantly modulated by the inducible knock-down of ALK and STAT3. To evaluate the functional role of differentially expressed miRNAs, we forced their expression in ALK+ Anaplastic Large Cell Lymphoma cells, and monitored their influence after STAT3 depletion. We found that the expression of miR-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 miR-17~92 interferes with STAT3 knock-down in vivo. High expression levels of miR-17~92 cluster resulted in down-regulation of BIM and TGFbetaRII proteins, suggesting that their targeting might mediate resistance to STAT3 knock-down in Anaplastic Large Cell Lymphoma cells. We speculate that miR-17~92 cluster is involved in the lymphomagenesis of STAT3+ ALCL, and that its inhibition might represent an alternative avenue to interfere with ALK signaling in Anaplastic Large Cell Lymphomas.