title: Transgenic mice overexpressing arginase 1 in monocytic cell lineage are affected by lympho-myeloproliferative disorders and disseminated intravascular coagulation.
abstract: Arginase (ARG) is a metabolic enzyme present in two isoforms that hydrolyze l-arginine to urea and ornithine. In humans, ARG isoform 1 is also expressed in cells of the myeloid lineage. ARG activity promotes tumour growth and inhibits T lymphocyte activation. However, the two ARG transgenic mouse lines produced so far failed to show such effects. We have generated, in two different genetic backgrounds, transgenic mice constitutively expressing ARG1 under the control of the CD68 promoter in macrophages and monocytes. Both heterozygous and homozygous transgenic mice showed a relevant increase in mortality at early age, compared with wild-type siblings (67/267 and 48/181 versus 8/149, respectively, both P < 0.005). This increase was due to high incidence of haematologic malignancies, in particular myeloid leukaemia, myeloid dysplasia, lymphomas and disseminated intravascular coagulation (DIC), diseases that were absent in wild-type mice. Atrophy of lymphoid organs due to reduction in T-cell compartment was also detected. Our results indicate that ARG activity may participate in the pathogenesis of lymphoproliferative and myeloproliferative disorders, suggest the involvement of alterations of L-arginine metabolism in the onset of DIC and confirm a role for the enzyme in regulating T-cell homeostasis.
authors.affiliation: Department of Haematology and Oncology, IRCCS AOU San Martino-IST National Institute for Cancer Research, Genova 16132, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Astigiano
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova 16132, Italy, Present address: IIT-The Italian Institute of Technology, Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Morini
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova 16132, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Damonte
authors.affiliation: Department of Haematology and Oncology, IRCCS AOU San Martino-IST National Institute for Cancer Research, Genova 16132, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Fraternali Orcioni
authors.affiliation: Laboratory for the Study of Inborn Errors of Metabolism, Istituto Giannina Gaslini, Genova 16100, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Cassanello
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova 16132, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Puglisi
authors.affiliation: Department of Biotechnology and Life Sciences, University of Insubria, Varese 21100, Italy, Department of Oncology, IRCCS MultiMedica, 20099 Sesto San Giovanni, Milan, Italy and.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Noonan
authors.affiliation: Department of Pathology and Diagnostic, University Hospital, Verona 37100, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Department of Haematology and Oncology, IRCCS AOU San Martino-IST National Institute for Cancer Research, Genova 16132, Italy, Department of Experimental Medicine, University of Genova, Genova 16132, Italy, ottavia.barbieri@unige.it ottaviabarbieri@yahoo.it.
authors.forename: Ottavia
authors.initials: O
authors.lastname: Barbieri
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D005260:Female; D015870:Gene Expression; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D009000:Monocytes / Q000201:enzymology*; D009196:Myeloproliferative Disorders / Q000201:enzymology* / Q000473:pathology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology
chemical_list: C544448:Arg1 protein, mouse; D001119:Arginase