ArticleThe Journal of experimental medicine2015
Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress.
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Article in The Journal of experimental medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35citing papers in PubMed
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35 citing papers in PubMed, 57 citations in OpenAlex.
- Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome.Blood · 2017Trial
- A guide to B cell metabolism.Nature reviews. Immunology · 2026Review
- Energy Homeostasis Disruption in Neurological Disorders: Mitochondrial Dysfunction, High-Energy Phosphate Transfer, and Extracellular ATP-Dependent Purinergic Dysregulation.International journal of molecular sciences · 2026Review
- Mitochondrial AK3 inhibits nuclear β-catenin localization and its activation through enhancing mitochondrial activity.Cell death & disease · 2026Article
- Case Report: Novel AK2 variant causing reticular dysgenesis with hemophagocytic lymphohistiocytosis-like syndrome and invasive aspergillosis.Frontiers in immunology · 2026Article
- AK2-Deficient Mice Recapitulate Impaired Lymphopoiesis of Reticular Dysgenesis Patients, but Also Lack Erythropoiesis.European journal of immunology · 2025Article
- The transcription factors Tfeb and Tfe3 are required for survival and embryonic development of pancreas and liver in zebrafish.PLoS genetics · 2025Article
- A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations.Blood · 2025Article
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- Adenylate kinase phosphate energy shuttle underlies energetic communication in flagellar axonemes.Science China. Life sciences · 2024Article
- TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress.Nature communications · 2024Article
- Zebrafish: A Relevant Genetic Model for Human Primary Immunodeficiency (PID) Disorders?International journal of molecular sciences · 2023Review
- Regulation of Adenine Nucleotide Metabolism by Adenylate Kinase Isozymes: Physiological Roles and Diseases.International journal of molecular sciences · 2023Review
- Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation.JCI insight · 2022Article
- Review
- Investigation of Protein Biomarkers and Oxidative Stress in Pinirampus pirinampu Exposed to Mercury Species from the Madeira River, Amazon-Brazil.Biological trace element research · 2022Article
- Review
- A connexin/ifi30 pathway bridges HSCs with their niche to dampen oxidative stress.Nature communications · 2021Article
- Adenylate kinase 2 expression and addiction in T-ALL.Blood advances · 2021Article
- AK2 Promotes the Migration and Invasion of Lung Adenocarcinoma by Activating TGF-β/Smad PathwayFrontiers in pharmacology · 2021Article
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Authors and funding
21 authors at 12 institutions in 7 countries.
Alberto RissoneDisorders 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.
Katja Gabriele WeinachtDivision 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.
Giancarlo la MarcaDepartment of Neurosciences, Psychology, Pharmacology, and Child Health, University of Florence, 51039 Florence, Italy Meyer Children's University Hospital, 50141 Florence, Italy.
Kevin BishopDisorders 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.
Elisa GiocaliereMeyer Children's University Hospital, 50141 Florence, Italy.
Jayashree JagadeeshDisorders 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.
Kerstin FelgentreffDivision of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
Kerry DobbsDivision of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
Waleed Al-HerzDepartment 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.
Marypat JonesDisorders 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.
Settara ChandrasekharappaDisorders 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.
Martha KirbyDisorders 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.
Stephen WincovitchDisorders 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.
Karen Lyn SimonDisorders 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.
Yuval ItanSt. Giles Laboratory of Human Genetics of Infectious Disease, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
Alex DeVineDivision of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
Thorsten SchlaegerDivision of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
Axel SchambachDivision of Hematology/Oncology and Division of Immunology, Boston Children's Hospital, Boston, MA 02115 Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
Raman SoodDisorders 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.
Luigi D NotarangeloDivision 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.
Fabio CandottiDisorders 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.
National Human Genome Research Institute · USPalmetto Hematology Oncology · USCancer Genetics (United States) · USGenomics (United Kingdom) · GBHematology Oncology Associates · USNational Institutes of Health · USHarvard University · USKuwait University · KWMedizinische Hochschule Hannover · DEMeyer Children's Hospital · ITRockefeller University · USUniversity of Florence · IT
Funding
Training of Clinical Investigators in Primary Immune DeficienciesU54AI082973 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PAI, SUNG-YUN · 2009 to 2023
$23.3MNHGRI/DIR Cytogenetics and Microscopy CoreZICHG200348 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI WINCOVITCH, STEPHEN · 2010 to 2025
$20.3MPATHOPHYSIOLOGY OF HUMAN BLOOD CELLST32HL007574 · NHLBI · CHILDREN'S HOSPITAL BOSTON · PI Daniel Evan Bauer · 1985 to 2026
$18.4MNHGRI/DIR Genomics CoreZICHG200346 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI CHANDRASEKHARAPPA, SETTARA · 2010 to 2025
$14.5MPOSITIONAL CLONING OF THE MEN1 GENEZIAHG000029 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI CHANDRASEKHARAPPA, SETTARA · 2009 to 2025
$13.3MNHGRI/DIR Zebrafish CoreZICHG200351 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI SOOD, RAMAN · 2015 to 2025
$12.1MModeling and correcting human SCID using patient-derived iPS cellsR01AI100887 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI MANIS, JOHN P · 2012 to 2020
$4.5MNHGRI/DIR Zebrafish CoreZIGHG200351 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI SOOD, RAMAN · 2010 to 2014
$3.9MIntramural NIH HHSNHLBI NIH HHS T32 HL007574NIAID NIH HHS 1U54AI082973NIAID NIH HHS 5R01AI100887NIAID NIH HHS R01 AI100887NIAID NIH HHS U54 AI082973
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.
Indexed as
Acridine OrangeAdenylate KinaseAnimalsAntioxidantsApoptosisAzo CompoundsBase SequenceCell DifferentiationComputational BiologyDNA PrimersHematopoietic Stem CellsImmunohistochemistryIn Situ Nick-End LabelingLeukopeniaMolecular Sequence DataNaphthalenesAcridine OrangeAdenylate Kinaseadenylate kinase 2AntioxidantsAzo CompoundsDNA PrimersNaphthalenesSudan Black B
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