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Antioxidant Treatment Rescues Hematopoietic Phenotypes in Different Models of Adenylate Kinase 2 Deficiency

Tuesday, September 23, 2014 — Poster Session III

12:00 p.m. – 2:00 p.m.

FAES Academic Center



* FARE Award Winner


  • Alber Rissone
  • Katja Weinacht
  • Kevin Bishop
  • Jaya Jagadeesh
  • Maryp Jones
  • Setta Chandrasekharappa
  • Raman Sood
  • Luigi Notarangelo
  • Fabio Candotti


Adenylate kinases (AKs) are phosphotransferase enzymes that regulate the cellular adenine nucleotide composition and have critical roles in energy homeostasis in 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). RD is characterized by a maturation arrest in the myeloid and lymphoid lineage leading to early onset, recurrent and overwhelming infections. To gain insights 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 resulted in severe impairment of hematopoiectic stem cells (HSC) development associated with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and had an energy depleted adenine nucleotide profile. Importantly, 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 cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress and point to the potential of antioxidants as supportive therapeutic modality for patients affected by RD.

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