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J Exp Med. 2015 Jul 27;212(8):1185-202. doi: 10.1084/jem.20141286. Epub 2015 Jul 6.

Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress.

Author information

1
Disorders of Immunity Section, Genetics and Molecular Biology Branch; Zebrafish Core and Oncogenesis and Development Section, Translational and Functional Genomics Branch; Genomics Core, Cancer Genetics and Comparative Genomics Branch; Division of Intramural Research Flow Cytometry Core; and Cytogenetics and Microscopy Core, Genetic Disease Research Branch; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
2
Division of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
3
Department of Neurosciences, Psychology, Pharmacology, and Child Health, University of Florence, 51039 Florence, Italy Meyer Children's University Hospital, 50141 Florence, Italy.
4
Meyer Children's University Hospital, 50141 Florence, Italy.
5
Division of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
6
Department of Pediatrics, Faculty of Medicine, Kuwait University, 13110 Kuwait City, Kuwait Allergy and Clinical Immunology Unit, Pediatric Department, Al-Sabah Hospital, 70459 Kuwait City, Kuwait.
7
St. Giles Laboratory of Human Genetics of Infectious Disease, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
8
Division of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115 Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
9
Disorders of Immunity Section, Genetics and Molecular Biology Branch; Zebrafish Core and Oncogenesis and Development Section, Translational and Functional Genomics Branch; Genomics Core, Cancer Genetics and Comparative Genomics Branch; Division of Intramural Research Flow Cytometry Core; and Cytogenetics and Microscopy Core, Genetic Disease Research Branch; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 Disorders of Immunity Section, Genetics and Molecular Biology Branch; Zebrafish Core and Oncogenesis and Development Section, Translational and Functional Genomics Branch; Genomics Core, Cancer Genetics and Comparative Genomics Branch; Division of Intramural Research Flow Cytometry Core; and Cytogenetics and Microscopy Core, Genetic Disease Research Branch; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
10
Division of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115 Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 Fabio.Candotti@chuv.ch Luigi.Notarangelo@childrens.harvard.edu.
11
Disorders of Immunity Section, Genetics and Molecular Biology Branch; Zebrafish Core and Oncogenesis and Development Section, Translational and Functional Genomics Branch; Genomics Core, Cancer Genetics and Comparative Genomics Branch; Division of Intramural Research Flow Cytometry Core; and Cytogenetics and Microscopy Core, Genetic Disease Research Branch; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 Division of Immunology and Allergy, University Hospital of Lausanne, 1011 Lausanne, Switzerland Fabio.Candotti@chuv.ch Luigi.Notarangelo@childrens.harvard.edu.

Abstract

Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD.

PMID:
26150473
PMCID:
PMC4516804
DOI:
10.1084/jem.20141286
[Indexed for MEDLINE]
Free PMC Article

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