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.

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

SPACCAROTELLA, ELISA;PELLEGRINO, Elisa;TAULLI, Riccardo;PROVERO, Paolo;DI CUNTO, Ferdinando;MEDICO, Enzo;INGHIRAMI, Giorgio;PIVA, Roberto
2014-01-01

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.
2014
99
1
116
124
http://www.haematologica.org/content/99/1/116.long
PERIPHERAL T-CELL; SIGNALING PATHWAY; STAT3 ACTIVATION; DOWN-REGULATION; LUNG-CANCER; KINASE; EXPRESSION; TARGET; INHIBITOR; GENE
Elisa Spaccarotella; Elisa Pellegrino; Manuela Ferracin; Cristina Ferreri; Giuditta Cuccuru; Cuiling Liu; Javeed Iqbal; Daniela Cantarella; Riccardo ...espandi
File in questo prodotto:
File Dimensione Formato  
2014-STAT3-mediated activation.pdf

Accesso aperto

Tipo di file: PDF EDITORIALE
Dimensione 510.61 kB
Formato Adobe PDF
510.61 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/136677
Citazioni
  • ???jsp.display-item.citation.pmc??? 21
  • Scopus 45
  • ???jsp.display-item.citation.isi??? 43
social impact