Esid 2014 oral presentations: AK-2 Prevents From Oxidative Stress During HSC Development and Hematopoietic Differentiation.

Adenylate kinase-2 (AK2) is a mitochondrial phosphotransferase enzyme that regulates the cellular adenine nucleotide composition and has a critical role in cell energy homeostasis. In humans, mutations of the AK2 gene are responsible for reticular dysgenesis (RD), one of the most profound forms of severe combined immunodeficiency (SCID). To gain insights into the pathophysiology of RD, we studied the effects ofAK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of a patient affected with RD. In zebrafish, AK2 deficiency resulted in severe impairment of hematopoietic stem cells (HSC) development associated with increased levels of reactive oxygen species (ROS), oxidative stress and apoptosis. AK2-deficient iPSCs showed abnormalities in adenine nucleotide levels and recapitulated the characteristic granulocytic maturation arrest at the promyelocyte stage observed in the bone marrow of RD patients. Importantly, antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2-mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Overall, our results support a mechanistic hypothesis involving abnormal redox state in the HSCs and multilineage abnormalities observed in AK2 deficiency and point to the potential of antioxidants as supportive therapeutic modality for patients affected by RD.