title: Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells.
abstract: Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34(+) cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;
authors.forename: Min
authors.identifier: http://orcid.org/0000-0002-4191-4787
authors.initials: M
authors.lastname: Lu
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;
authors.forename: Lijuan
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Division of Biostatistics, Department of Population Health and Department of Environmental Medicine, New York University School of Medicine, New York, NY; and.
authors.forename: Tsivia
authors.initials: T
authors.lastname: Hochman
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;
authors.forename: Laetizia
authors.initials: L
authors.lastname: Bizzari
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;
authors.forename: Daniel
authors.initials: D
authors.lastname: Aruch
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;
authors.forename: Jane
authors.initials: J
authors.lastname: Lew
authors.affiliation: Cellular Therapy Laboratory, New York Blood Center, New York, NY.
authors.forename: Rona
authors.initials: R
authors.lastname: Weinberg
authors.affiliation: Division of Biostatistics, Department of Population Health and Department of Environmental Medicine, New York University School of Medicine, New York, NY; and.
authors.forename: Judith D
authors.initials: JD
authors.lastname: Goldberg
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology*; D060833:Cellular Microenvironment / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D055728:Primary Myelofibrosis / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins