title: Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia.
abstract: Infiltration of the central nervous system is a severe trait of T cell acute lymphoblastic leukemia. Inhibition of CXC chemokine receptor 4 significantly ameliorates T cell acute lymphoblastic leukemia in murine models of the disease; however, signaling by CXC chemokine receptor 4 is important in limiting the divagation of peripheral blood mononuclear cells out of the perivascular space into the central nervous system parenchyma. Therefore, Inhibition of CXC chemokine receptor 4 potentially may untangle T cell acute lymphoblastic leukemia cells from retention outside the brain. Here, we show that leukemic lymphoblasts massively infiltrate cranial bone marrow, with diffusion to the meninges without invasion of the brain parenchyma, in mice that underwent xenotransplantation with human T cell acute lymphoblastic leukemia cells or that developed leukemia from transformed hematopoietic progenitors. We tested the hypothesis that T cell acute lymphoblastic leukemia neuropathology results from meningeal infiltration through CXC chemokine receptor 4-mediated bone marrow colonization. Inhibition of leukemia engraftment in the bone marrow by pharmacologic CXC chemokine receptor 4 antagonism significantly ameliorated neuropathologic aspects of the disease. Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development. We hypothesize that lymphoblastic meningeal infiltration as a result of bone marrow colonization is responsible for the degenerative alterations of the neuroparenchyma as well as the alteration of cerebrospinal fluid drainage in T cell acute lymphoblastic leukemia xenografts. Therefore, CXC chemokine receptor 4 may constitute a pharmacologic target for T cell acute lymphoblastic leukemia neuropathology.
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland;
authors.forename: Tanja Rezzonico
authors.initials: TR
authors.lastname: Jost
authors.affiliation: Department of Women's and Children's Health, Laboratory of Pediatric Oncohematology, University of Padova, Padova, Italy;
authors.forename: Chiara
authors.initials: C
authors.lastname: Borga
authors.affiliation: VIB11 Center for the Biology of Disease, Center for Human Genetics, KU Leuven, Leuven, Belgium; VIB InfraMouse, KU Leuven, Leuven, Belgium;
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland;
authors.forename: Andrea
authors.initials: A
authors.lastname: Romagnani
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland;
authors.forename: Lisa
authors.initials: L
authors.lastname: Perruzza
authors.affiliation: VIB11 Center for the Biology of Disease, Center for Human Genetics, KU Leuven, Leuven, Belgium; VIB InfraMouse, KU Leuven, Leuven, Belgium;
authors.forename: Lorna
authors.initials: L
authors.lastname: Omodho
authors.affiliation: Pediatric Clinic, M. Tettamanti Research Center, University of Milano Bicocca Monza, Italy;
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.affiliation: Pediatric Clinic, M. Tettamanti Research Center, University of Milano Bicocca Monza, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto-IRCCS, Padova, Italy;
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland;
authors.forename: Marcus
authors.initials: M
authors.lastname: Thelen
authors.affiliation: Department of Women's and Children's Health, Laboratory of Pediatric Oncohematology, University of Padova, Padova, Italy;
authors.forename: Geertruy
authors.initials: G
authors.lastname: Te Kronnie
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland; Department of Medical Biotechnology and Translational Medicine, University of Milano, Milan, Italy; and Istituto Nazionale di Genetica Molecolare, Milan, Italy fabio.grassi@irb.usi.ch.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
mesh_terms: D000293:Adolescent; D000818:Animals; D001596:Benzylamines; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D000080027:Cyclams; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000196:embryology; D008297:Male; D008578:Meninges / Q000187:drug effects / Q000473:pathology; D051379:Mice; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D051880:Receptors, Notch; C088327:plerixafor
keywords: CCR6; CCR7; blood-brain barrier; meninges; neuropathology