title: Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling.
abstract: Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by α-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes α-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile.
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Yuh-Ying
authors.initials: YY
authors.lastname: Yeh
authors.affiliation: Department of Biomedical Informatics.
authors.forename: Hatice Gulcin
authors.initials: HG
authors.lastname: Ozer
authors.affiliation: Center for Biostatistics, and.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lehman
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.affiliation: Center for Biostatistics, and.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Hematology, Department of Internal Medicine, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Division of Hematology, Department of Internal Medicine, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D055354:Exosomes / Q000235:genetics* / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D059467:Transcriptome; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D035683:MicroRNAs; D011947:Receptors, Antigen, B-Cell
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