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.
E. Spaccarotella, E. Pellegrino, M. Ferracin, C. Ferreri, G. Cuccuru, C. Liu, et al. (2014). STAT3-mediated activation of microRNA cluster 17 92 promotes proliferation and survival of ALK positive anaplastic large cell lymphoma. HAEMATOLOGICA, 99, 116-124 [10.3324/haematol.2013.088286].
STAT3-mediated activation of microRNA cluster 17 92 promotes proliferation and survival of ALK positive anaplastic large cell lymphoma
FERRACIN, MANUELA;
2014
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.