title: The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes.
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.
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bomben
authors.forename: S
authors.initials: S
authors.lastname: Gobessi
authors.forename: M
authors.initials: M
authors.lastname: Dal Bo
authors.forename: S
authors.initials: S
authors.lastname: Volinia
authors.forename: D
authors.initials: D
authors.lastname: Marconi
authors.forename: E
authors.initials: E
authors.lastname: Tissino
authors.forename: D
authors.initials: D
authors.lastname: Benedetti
authors.forename: A
authors.initials: A
authors.lastname: Zucchetto
authors.forename: D
authors.initials: D
authors.lastname: Rossi
authors.forename: G
authors.initials: G
authors.lastname: Gaidano
authors.forename: G
authors.initials: G
authors.lastname: Del Poeta
authors.forename: L
authors.initials: L
authors.lastname: Laurenti
authors.forename: D G
authors.initials: DG
authors.lastname: Efremov
authors.forename: V
authors.initials: V
authors.lastname: Gattei
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051217:Toll-Like Receptor 9 / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C408982:CPG-oligonucleotide; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C000715470:MAS1 protein, human; C568997:MIR17HG, human; D035683:MicroRNAs; D009838:Oligodeoxyribonucleotides; D000090063:Proto-Oncogene Mas; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human