title: The regulation of tumor-suppressive microRNA, miR-126, in chronic lymphocytic leukemia.
abstract: The introduction of miR profiling of chronic lymphocytic leukemia (CLL) patients with different cytogenetic profiles and responses to therapy has allowed incorporation of important miR-mRNA interactions into the understanding of disease biology. In this study, we performed miR expression analysis using NanoString nCounter to discover differentially regulated miRs after therapy with the Bruton tyrosine kinase inhibitor ibrutinib. Of the differentially regulated miRs in the discovery set, miR-29c and miR-126 were confirmed using real-time PCR to be upregulated in CLL patient cells with ibrutinib therapy. In the validation set, an inverse correlation was observed between miR-126 levels and expression of its putative target p85β, an isoform of the phosphoinositide 3-kinase p85 regulatory subunit. We found that mRNA for the host gene EGFL7, primary unprocessed miR-126, and mature miR-126 are all downregulated in CLL cells compared to normal B cells. Patients in later stages of disease have a greater decrease in miR-126 expression compared to treatment-naive patients, indicating that lower miR-126 levels may associate with disease progression. Overexpression of miR-126 in leukemia cell lines significantly downregulates p85β expression and decreases activation of prosurvival mitogen-activated protein kinase (MAPK) signaling. These results implicate miR-126 in the pathology of CLL.
authors.affiliation: Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio.|Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Daphne
authors.initials: D
authors.lastname: Guinn
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fabian
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Flynn
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Jaglowski
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D015536:Down-Regulation; D066255:EGF Family of Proteins; D016228:Endothelial Growth Factors / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use
chemical_list: D000225:Adenine; D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; D016228:Endothelial Growth Factors; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C527877:EGFL7 protein, human; C527111:MIRN126 microRNA, human; C551803:ibrutinib; C560566:phosphoinositol-3 kinase regulatory subunit 2, human
keywords: 
  CLL
  ; ibrutinib; microRNAs