title: Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress.
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.
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rissone
authors.affiliation: 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.
authors.forename: Katja Gabriele
authors.initials: KG
authors.lastname: Weinacht
authors.affiliation: Department of Neurosciences, Psychology, Pharmacology, and Child Health, University of Florence, 51039 Florence, Italy Meyer Children's University Hospital, 50141 Florence, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bishop
authors.affiliation: Meyer Children's University Hospital, 50141 Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giocaliere
authors.affiliation: 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.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Jagadeesh
authors.affiliation: Division of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Felgentreff
authors.affiliation: Division of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Kerry
authors.initials: K
authors.lastname: Dobbs
authors.affiliation: 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.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.affiliation: 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.
authors.forename: Marypat
authors.initials: M
authors.lastname: Jones
authors.affiliation: 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.
authors.forename: Settara
authors.initials: S
authors.lastname: Chandrasekharappa
authors.affiliation: 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.
authors.forename: Martha
authors.initials: M
authors.lastname: Kirby
authors.affiliation: 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.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wincovitch
authors.affiliation: 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.
authors.forename: Karen Lyn
authors.initials: KL
authors.lastname: Simon
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Disease, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: Division of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Alex
authors.initials: A
authors.lastname: DeVine
authors.affiliation: Division of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlaeger
authors.affiliation: 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.
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.affiliation: 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.
authors.forename: Raman
authors.initials: R
authors.lastname: Sood
authors.affiliation: 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.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: 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.
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
mesh_terms: D000165:Acridine Orange; D000263:Adenylate Kinase / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001391:Azo Compounds; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007970:Leukopenia / Q000201:enzymology* / Q000503:physiopathology*; D008969:Molecular Sequence Data; D009281:Naphthalenes; D018384:Oxidative Stress / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D016511:Severe Combined Immunodeficiency / Q000201:enzymology* / Q000503:physiopathology*; D015027:Zebrafish
chemical_list: D000975:Antioxidants; D001391:Azo Compounds; D017931:DNA Primers; D009281:Naphthalenes; C016118:Sudan Black B; D000263:Adenylate Kinase; C110938:adenylate kinase 2; D000165:Acridine Orange