The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes

Luca Laurenti, R Bomben, S Gobessi, M Dal Bo, S Volinia, D Marconi, E Tissino, D Benedetti, A Zucchetto, D Rossi, G Gaidano, G Del Poeta, Dg Efremov, V. Gattei

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Chronic lymphocytic leukemia (CLL) cells from clinically aggressive cases have a greater capacity to respond to external microenvironmental stimuli, including those transduced through Toll-like-receptor-9 (TLR9). Concomitant microRNA and gene expression profiling in purified CLL cells (n=17) expressing either unmutated (UM) or mutated (M) IGHV genes selected microRNAs from the miR-17∼92 family as significantly upregulated and in part responsible for modifications in the gene expression profile of UM CLL cells stimulated with the TLR9 agonist CpG. Notably, the stable and sustained upregulation of miR-17∼92 microRNAs by CpG was preceded by a transient induction of the proto-oncogene MYC. The enforced expression of miR-17, a major member from this family, reduced the expression of the tumor suppressor genes E2F5, TP53INP1, TRIM8 and ZBTB4, and protected cells from serum-free-induced apoptosis (P ≤ 0.05). Consistently, transfection with miR-17∼92 family antagomiRs reduced Bromo-deoxy-uridine incorporation in CpG-stimulated UM CLL cells. Finally, miR-17 expression levels, evaluated in 83 CLL samples, were significantly higher in UM (P=0.03) and ZAP-70(high) (P=0.02) cases. Altogether, these data reveal a role for microRNAs of the miR-17∼92 family in regulating pro-survival and growth-promoting responses of CLL cells to TLR9 triggering. Overall, targeting of this pathway may represent a novel therapeutic option for management of aggressive CLL.
Original languageEnglish
Pages (from-to)1584-1593
Number of pages10
JournalLeukemia
Volume26
DOIs
Publication statusPublished - 2012

Keywords

  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Humans
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • MicroRNAs
  • Mutation
  • Oligodeoxyribonucleotides
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 9
  • Tumor Cells, Cultured
  • Tumor Markers, Biological
  • ZAP-70 Protein-Tyrosine Kinase

Fingerprint

Dive into the research topics of 'The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes'. Together they form a unique fingerprint.

Cite this