title: CLL cells respond to B-Cell receptor stimulation with a microRNA/mRNA signature associated with MYC activation and cell cycle progression.
abstract: Chronic lymphocytic leukemia (CLL) is a disease with variable clinical outcome. Several prognostic factors such as the immunoglobulin heavy chain variable genes (IGHV) mutation status are linked to the B-cell receptor (BCR) complex, supporting a role for triggering the BCR in vivo in the pathogenesis. The miRNA profile upon stimulation and correlation with IGHV mutation status is however unknown. To evaluate the transcriptional response of peripheral blood CLL cells upon BCR stimulation in vitro, miRNA and mRNA expression was measured using hybridization arrays and qPCR. We found both IGHV mutated and unmutated CLL cells to respond with increased expression of MYC and other genes associated with BCR activation, and a phenotype of cell cycle progression. Genome-wide expression studies showed hsa-miR-132-3p/hsa-miR-212 miRNA cluster induction associated with a set of downregulated genes, enriched for genes modulated by BCR activation and amplified by Myc. We conclude that BCR triggering of CLL cells induces a transcriptional response of genes associated with BCR activation, enhanced cell cycle entry and progression and suggest that part of the transcriptional profiles linked to IGHV mutation status observed in isolated peripheral blood are not cell intrinsic but rather secondary to in vivo BCR stimulation.
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology; Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
authors.forename: Valerie
authors.initials: V
authors.lastname: Pede
authors.forename: Ans
authors.initials: A
authors.lastname: Rombout
authors.forename: Jolien
authors.initials: J
authors.lastname: Vermeire
authors.forename: Evelien
authors.initials: E
authors.lastname: Naessens
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.forename: Nore
authors.initials: N
authors.lastname: Robberecht
authors.forename: Hanne
authors.initials: H
authors.lastname: Vanderstraeten
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Jan
authors.initials: J
authors.lastname: Philippé
authors.forename: Bruno
authors.initials: B
authors.lastname: Verhasselt
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D055106:Genome-Wide Association Study; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D005810:Multigene Family; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics* / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000888:Antibodies, Anti-Idiotypic; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C547077:MIRN132 microRNA, human; C551411:MIRN212 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell
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