title: Mouse models of mantle cell lymphoma, complex changes in gene expression and phenotype of engrafted MCL cells: implications for preclinical research.
abstract: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma (NHL) associated with poor prognosis. Animal models of MCL are scarce. We established and characterized various in vivo models of metastatic human MCL by tail vein injection of either primary cells isolated from patients with MCL or established MCL cell lines (Jeko-1, Mino, Rec-1, Hbl-2, and Granta-519) into immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. MCL infiltration was assessed with immunohistochemistry (tissues) and flow cytometry (peripheral blood). Engraftment of primary MCL cells was observed in 7 out of 12 patient samples. The pattern of engraftment of primary MCL cells varied from isolated involvement of the spleen to multiorgan infiltration. On the other hand, tumor engraftment was achieved in all five MCL cell lines used and lymphoma involvement of murine bone marrow, spleen, liver, and brain was observed. Overall survival of xenografted mice ranged from 22 ± 1 to 54 ± 3 days depending on the cell line used. Subsequently, we compared the gene expression profile (GEP) and phenotype of the engrafted MCL cells compared with the original in vitro growing cell lines (controls). We demonstrated that engrafted MCL cells displayed complex changes of GEP, protein expression, and sensitivity to cytotoxic agents when compared with controls. We further demonstrated that our MCL mouse models could be used to test the therapeutic activity of systemic chemotherapy, monoclonal antibodies, or angiogenesis inhibitors. The characterization of MCL murine models is likely to aid in improving our knowledge in the disease biology and to assist scientists in the preclinical and clinical development of novel agents in relapsed/refractory MCL patients.
authors.affiliation: 1] First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic [2] First Department of Medicine, Clinical Department of Hematology of the General University Hospital, Charles University in Prague, Prague, Czech Republic.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Klanova
authors.affiliation: Medical Faculty Hradec Kralove, Institute of Histology and Embryology, Charles University, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Soukup
authors.affiliation: First Faculty of Medicine, Institute of Pathology, Charles University in Prague.
authors.forename: Radek
authors.initials: R
authors.lastname: Jaksa
authors.affiliation: 1] First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic [2] First Department of Medicine, Clinical Department of Hematology of the General University Hospital, Charles University in Prague, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Molinsky
authors.affiliation: 1] First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic [2] First Department of Medicine, Clinical Department of Hematology of the General University Hospital, Charles University in Prague, Prague, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Lateckova
authors.affiliation: First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Bokang C L
authors.initials: BC
authors.lastname: Maswabi
authors.affiliation: First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Prukova
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Brezinova
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Kyra
authors.initials: K
authors.lastname: Michalova
authors.affiliation: 1] First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic [2] First Department of Medicine, Clinical Department of Hematology of the General University Hospital, Charles University in Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Vockova
authors.affiliation: Department of Medical Oncology and Immunology, Cancer Cell Center, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernandez-Ilizaliturri
authors.affiliation: First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Kulvait
authors.affiliation: First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Zivny
authors.affiliation: First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Vokurka
authors.affiliation: First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Necas
authors.affiliation: 1] First Department of Medicine, Clinical Department of Hematology of the General University Hospital, Charles University in Prague, Prague, Czech Republic [2] Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trneny
authors.affiliation: 1] First Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic [2] First Department of Medicine, Clinical Department of Hematology of the General University Hospital, Charles University in Prague, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
mesh_terms: D000368:Aged; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D013154:Spleen / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit