title: Bone marrow transplantation improves the outcome of Atm-deficient mice through the migration of ATM-competent cells.
abstract: Ataxia telangiectasia (A-T) is a highly pleiotropic disorder. Patients suffer from progressive neurodegeneration, severe bronchial complications, immunodeficiency, hypersensitivity to radiotherapy and elevated risk of malignancies. Leukemia and lymphoma, along with lung failure, are the main causes of morbidity and mortality in A-T patients. At present, no effective therapy for A-T exists. One promising therapeutic approach is bone marrow transplantation (BMT) that is already used as a curative therapy for other genomic instability syndromes. We used an established clinically relevant non-myeloablative host-conditioning regimen and transplanted green fluorescent protein (GFP)-expressing ataxia telangiectasia mutated (ATM)-competent bone marrow-derived cells (BMDCs) into Atm-deficient mice. GFP expression allowed tracking of the potential migration of the cells into the tissues of recipient animals. Donor BMDCs migrated into the bone marrow, blood, thymus, spleen and lung tissue of Atm-deficient mice showing an ATM-competent phenotype. BMT inhibited thymic lymphomas, normalized T-lymphocyte populations, improved weight gain and rearing activity of Atm-deficient mice. In contrast, no GFP(+) cells were found in the cerebellum or cerebrum, and we detected decreased size index in MRI imaging of the cerebellum in 8-month-old transplanted Atm-deficient mice in comparison to wild-type mice. The repopulation with ATM-competent BMDCs is associated with a prolonged lifespan and significantly improved the phenotype of Atm-deficient mice.
authors.affiliation: Department of Allergy, Pulmonology, and Cystic Fibrosis, Children’s Hospital, Goethe University, Frankfurt, Germany. Julia.Pietzner@kgu.de
authors.forename: J
authors.initials: J
authors.lastname: Pietzner
authors.forename: P C
authors.initials: PC
authors.lastname: Baer
authors.forename: R P
authors.initials: RP
authors.lastname: Duecker
authors.forename: M B
authors.initials: MB
authors.lastname: Merscher
authors.forename: C
authors.initials: C
authors.lastname: Satzger-Prodinger
authors.forename: I
authors.initials: I
authors.lastname: Bechmann
authors.forename: A
authors.initials: A
authors.lastname: Wietelmann
authors.forename: D
authors.initials: D
authors.lastname: Del Turco
authors.forename: C
authors.initials: C
authors.lastname: Doering
authors.forename: S
authors.initials: S
authors.lastname: Kuci
authors.forename: P
authors.initials: P
authors.lastname: Bader
authors.forename: S
authors.initials: S
authors.lastname: Schirmer
authors.forename: S
authors.initials: S
authors.lastname: Zielen
authors.forename: R
authors.initials: R
authors.lastname: Schubert
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D064007:Ataxia Telangiectasia Mutated Proteins; D001812:Blood-Brain Barrier / Q000378:metabolism; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D046528:Chimerism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D036102:Peripheral Blood Stem Cell Transplantation; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases