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

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 for...

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Autores principales: Rissone, Alberto, Weinacht, Katja Gabriele, la Marca, Giancarlo, Bishop, Kevin, Giocaliere, Elisa, Jagadeesh, Jayashree, Felgentreff, Kerstin, Dobbs, Kerry, Al-Herz, Waleed, Jones, Marypat, Chandrasekharappa, Settara, Kirby, Martha, Wincovitch, Stephen, Simon, Karen Lyn, Itan, Yuval, DeVine, Alex, Schlaeger, Thorsten, Schambach, Axel, Sood, Raman, Notarangelo, Luigi D., Candotti, Fabio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516804/
https://www.ncbi.nlm.nih.gov/pubmed/26150473
http://dx.doi.org/10.1084/jem.20141286
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author Rissone, Alberto
Weinacht, Katja Gabriele
la Marca, Giancarlo
Bishop, Kevin
Giocaliere, Elisa
Jagadeesh, Jayashree
Felgentreff, Kerstin
Dobbs, Kerry
Al-Herz, Waleed
Jones, Marypat
Chandrasekharappa, Settara
Kirby, Martha
Wincovitch, Stephen
Simon, Karen Lyn
Itan, Yuval
DeVine, Alex
Schlaeger, Thorsten
Schambach, Axel
Sood, Raman
Notarangelo, Luigi D.
Candotti, Fabio
author_facet Rissone, Alberto
Weinacht, Katja Gabriele
la Marca, Giancarlo
Bishop, Kevin
Giocaliere, Elisa
Jagadeesh, Jayashree
Felgentreff, Kerstin
Dobbs, Kerry
Al-Herz, Waleed
Jones, Marypat
Chandrasekharappa, Settara
Kirby, Martha
Wincovitch, Stephen
Simon, Karen Lyn
Itan, Yuval
DeVine, Alex
Schlaeger, Thorsten
Schambach, Axel
Sood, Raman
Notarangelo, Luigi D.
Candotti, Fabio
author_sort Rissone, Alberto
collection PubMed
description 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.
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spelling pubmed-45168042016-01-27 Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress Rissone, Alberto Weinacht, Katja Gabriele la Marca, Giancarlo Bishop, Kevin Giocaliere, Elisa Jagadeesh, Jayashree Felgentreff, Kerstin Dobbs, Kerry Al-Herz, Waleed Jones, Marypat Chandrasekharappa, Settara Kirby, Martha Wincovitch, Stephen Simon, Karen Lyn Itan, Yuval DeVine, Alex Schlaeger, Thorsten Schambach, Axel Sood, Raman Notarangelo, Luigi D. Candotti, Fabio J Exp Med Article 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. The Rockefeller University Press 2015-07-27 /pmc/articles/PMC4516804/ /pubmed/26150473 http://dx.doi.org/10.1084/jem.20141286 Text en This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Rissone, Alberto
Weinacht, Katja Gabriele
la Marca, Giancarlo
Bishop, Kevin
Giocaliere, Elisa
Jagadeesh, Jayashree
Felgentreff, Kerstin
Dobbs, Kerry
Al-Herz, Waleed
Jones, Marypat
Chandrasekharappa, Settara
Kirby, Martha
Wincovitch, Stephen
Simon, Karen Lyn
Itan, Yuval
DeVine, Alex
Schlaeger, Thorsten
Schambach, Axel
Sood, Raman
Notarangelo, Luigi D.
Candotti, Fabio
Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress
title Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress
title_full Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress
title_fullStr Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress
title_full_unstemmed Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress
title_short Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress
title_sort reticular dysgenesis–associated ak2 protects hematopoietic stem and progenitor cell development from oxidative stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516804/
https://www.ncbi.nlm.nih.gov/pubmed/26150473
http://dx.doi.org/10.1084/jem.20141286
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