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.

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice

“…7 At the face of Purkinje cell loss and progressive lung destruction several studies have shown that BMDC are able to contribute to neogenesis of cerebellar Purkinje neurons or lung tissue regeneration and protection which is of special interest for a therapeutic approach for A-T. 8,9 In Atm-deficient mice, BMT significantly inhibited tumorigenesis and improved the immunity, weight gain and fitness. 10,11 Our results further showed the migration of CD31 +CD45-endothelial cells and EpCAM+ epithelial cells into the lung tissue of transplanted Atm-deficient mice. 10 However, BMT using a non-myeloablative host-conditioning regimen with cyclophosphamide (CP) and anti-thymocyte globulin did not result in full donor chimerism.…”

“…10,11 Our results further showed the migration of CD31 +CD45-endothelial cells and EpCAM+ epithelial cells into the lung tissue of transplanted Atm-deficient mice. 10 However, BMT using a non-myeloablative host-conditioning regimen with cyclophosphamide (CP) and anti-thymocyte globulin did not result in full donor chimerism. In addition, the engraftment of donor-derived cells into the lung tissue was low and no cells migrated into the cerebellum.…”

“…[12][13][14] Recently, we and others have demonstrated that BMT significantly improves the immunological phenotype, weight gain and fitness, and inhibits tumorigenesis in Atm-deficient mice. 10,11 However, BMT using a non-myeloablative host-conditioning regimen failed to reach a full donor chimerism. In addition, engraftment of donor-derived cells into the lung tissue was low, and no migrated cells could be found in the cerebellum.…”

“…In addition, the engraftment of donor-derived cells into the lung tissue was low and no cells migrated into the cerebellum. 10 Experience in the transplantation of A-T patients so far is limited and no transplantation strategy exists. [12][13][14] In other genomic instability syndromes, such as Fanconi anemia (FA), Nijmegen breakage syndrome (NBS) or DNA ligase IV deficiency, BMT has been successfully used.…”

Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation—what to do?

“…DSBs activate ATM (Ataxia-Telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3) kinases which phosphorylate as many as 700 proteins that transduce the DNA damage signal, arrest the cell cycle and start DNA repair or, if the damage cannot be repaired, activate apoptosis [2,3]. Unlike most other DNA damage, DNA DSBs directly threaten genomic integrity; thus, these repair processes are essential for preserving genomic structure, and reducing mutagenic risk and oncogenesis.…”