title: Extracellular vesicle miR-7977 is involved in hematopoietic dysfunction of mesenchymal stromal cells via poly(rC) binding protein 1 reduction in myeloid neoplasms.
abstract: The failure of normal hematopoiesis is observed in myeloid neoplasms. However, the precise mechanisms governing the replacement of normal hematopoietic stem cells in their niche by myeloid neoplasm stem cells have not yet been clarified. Primary acute myeloid leukemia and myelodysplastic syndrome cells induced aberrant expression of multiple hematopoietic factors including Jagged-1, stem cell factor and angiopoietin-1 in mesenchymal stem cells even in non-contact conditions, and this abnormality was reverted by extracellular vesicle inhibition. Importantly, the transfer of myeloid neoplasm-derived extracellular vesicles reduced the hematopoietic supportive capacity of mesenchymal stem cells. Analysis of extracellular vesicle microRNA indicated that several species, including miR-7977 from acute myeloid leukemia cells, were higher than those from normal CD34(+)cells. Remarkably, the copy number of miR-7977 in bone marrow interstitial fluid was elevated not only in acute myeloid leukemia, but also in myelodysplastic syndrome, as compared with lymphoma without bone marrow localization. The transfection of the miR-7977 mimic reduced the expression of the posttranscriptional regulator, poly(rC) binding protein 1, in mesenchymal stem cells. Moreover, the miR-7977 mimic induced aberrant reduction of hematopoietic growth factors in mesenchymal stem cells, resulting in decreased hematopoietic-supporting capacity of bone marrow CD34(+)cells. Furthermore, the reduction of hematopoietic growth factors including Jagged-1, stem cell factor and angiopoietin-1 were reverted by target protection of poly(rC) binding protein 1, suggesting that poly(rC) binding protein 1 could be involved in the stabilization of several growth factors. Thus, miR-7977 in extracellular vesicles may be a critical factor that induces failure of normal hematopoiesis via poly(rC) binding protein 1 suppression.
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Horiguchi
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan mkobune@sapmed.ac.jp.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kobune
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kikuchi
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Murata
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Murase
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iyama
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Kohichi
authors.initials: K
authors.lastname: Takada
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ono
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Tatekoshi
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kamihara
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Miyanishi
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Sawada
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kato
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D004268:DNA-Binding Proteins; D000067128:Extracellular Vesicles / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis / Q000235:genetics*; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D018716:Molecular Mimicry; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009367:Neoplasm Staging; D009843:Oligoribonucleotides / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D000072100:Jagged-1 Protein; C000613306:MIRN7977 microRNA, human; D035683:MicroRNAs; D009843:Oligoribonucleotides; C094604:PCBP1 protein, human; D016601:RNA-Binding Proteins; D019089:Stem Cell Factor