title: MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia.
abstract: High-level leukemia cell expression of micro-RNA 155 (miR-155) is associated with more aggressive disease in patients with chronic lymphocytic leukemia (CLL), including those cases with a low-level expression of ζ-chain-associated protein of 70 kD. CLL with high-level miR-155 expressed lower levels of Src homology-2 domain-containing inositol 5-phosphatase 1 and were more responsive to B-cell receptor (BCR) ligation than CLL with low-level miR-155. Transfection with miR-155 enhanced responsiveness to BCR ligation, whereas transfection with a miR-155 inhibitor had the opposite effect. CLL in lymphoid tissue expressed higher levels of miR155HG than CLL in the blood of the same patient. Also, isolated CD5(bright)CXCR4(dim) cells, representing CLL that had been newly released from the microenvironment, expressed higher levels of miR-155 and were more responsive to BCR ligation than isolated CD5(dim)CXCR4(bright) cells of the same patient. Treatment of CLL or normal B cells with CD40-ligand or B-cell-activating factor upregulated miR-155 and enhanced sensitivity to BCR ligation, effects that could be blocked by inhibitors to miR-155. This study demonstrates that the sensitivity to BCR ligation can be enhanced by high-level expression of miR-155, which in turn can be induced by crosstalk within the tissue microenvironment, potentially contributing to its association with adverse clinical outcome in patients with CLL.
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Liguang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA; Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic; and.
authors.forename: Marek
authors.initials: M
authors.lastname: Mraz
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Jessie-F
authors.initials: JF
authors.lastname: Fecteau
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Ghia
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Lei
authors.initials: L
authors.lastname: Bao
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Rassenti
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Karen
authors.initials: K
authors.lastname: Messer
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH, of the CLL Research Consortium.
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH, of the CLL Research Consortium.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D018956:CD5 Antigens / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D059016:Tumor Microenvironment; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018956:CD5 Antigens; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D019718:Receptors, CXCR4; D023201:CD40 Ligand; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D002118:Calcium