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

Haematologica. 2014 Jan;99(1):116-24. doi: 10.3324/haematol.2013.088286. Epub 2013 Aug 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / genetics
  • Cluster Analysis
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Lymphoma, Large-Cell, Anaplastic / metabolism*
  • Lymphoma, Large-Cell, Anaplastic / mortality
  • MicroRNAs / genetics*
  • Multigene Family*
  • RNA Interference
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Transcriptional Activation*


  • MicroRNAs
  • STAT3 Transcription Factor
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases