TY - JOUR
T1 - The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes
AU - Bomben, R.
AU - Gobessi, S.
AU - Dal Bo, M.
AU - Volinia, S.
AU - Marconi, D.
AU - Tissino, E.
AU - Benedetti, D.
AU - Zucchetto, A.
AU - Rossi, D.
AU - Gaidano, G.
AU - Del Poeta, G.
AU - Laurenti, Luca
AU - Efremov, D. G.
AU - Gattei, V.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Blotting, Western
KW - Cell Proliferation
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Leukemic
KW - Humans
KW - Immunoglobulin Heavy Chains
KW - Immunoglobulin Variable Region
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - MicroRNAs
KW - Mutation
KW - Oligodeoxyribonucleotides
KW - Oligonucleotide Array Sequence Analysis
KW - RNA, Messenger
KW - Real-Time Polymerase Chain Reaction
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Toll-Like Receptor 9
KW - Tumor Cells, Cultured
KW - Tumor Markers, Biological
KW - ZAP-70 Protein-Tyrosine Kinase
KW - Apoptosis
KW - Blotting, Western
KW - Cell Proliferation
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Leukemic
KW - Humans
KW - Immunoglobulin Heavy Chains
KW - Immunoglobulin Variable Region
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - MicroRNAs
KW - Mutation
KW - Oligodeoxyribonucleotides
KW - Oligonucleotide Array Sequence Analysis
KW - RNA, Messenger
KW - Real-Time Polymerase Chain Reaction
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Toll-Like Receptor 9
KW - Tumor Cells, Cultured
KW - Tumor Markers, Biological
KW - ZAP-70 Protein-Tyrosine Kinase
UR - http://hdl.handle.net/10807/40270
U2 - 10.1038/leu.2012.44
DO - 10.1038/leu.2012.44
M3 - Article
SN - 0887-6924
VL - 26
SP - 1584
EP - 1593
JO - Leukemia
JF - Leukemia
ER -