Induced Pluripotent Stem Cells From a Patient with Reticular Dysgenesis Recapitulate Defective Myelopoiesis in-Vitro: A Disease Model to Enhance Our Understanding of a Rare Disease.

Abstract 2142

Reticular dysgenesis (RD) is one of the most severe forms of combined immunodeficiency characterized by severe congenital neutropenia (SCN) and impaired lymphocyte development. Origin of the neutropenia is thought to be an early differentiation arrest at the promyelocte stage. Recently the disease has been mapped to mutations in the gene encoding for Adenylate Kinase 2 (AK2). Adenylate kinase 2 is a phosphokinase implicated in mitochondrial energy homeostasis. The exact mechanism, however, how a defect in this ubiquitously expressed enzyme selectively manifests in defective granulopoiesis and lymphopoiesis remains poorly understood. A significant obstacle to the study of rare diseases like Reticular Dysgenesis has been the inadequacy of animal models and limited availability of patient specimens.

We have successfully generated induced pluripotent stem cells (iPSCs) from a patient with Reticular Dysgenesis and proven genetic defect in Adenylate Kinase 2 (AK2). Myeloid precursors derived from the AK2-deficient iPSCs morphologically mimic the myeloid maturation arrest seen in the bone marrow of patients with this condition (Figure 1). We are currently using this in-vitro model as a platform to study the mechanisms underlying the maturation arrest on a cellular and molecular level.

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Summary: Here we report a pluripotent stem cell (iPSC)-based disease model for Reticular Dysgenesis. This model does not only accurately recapitulate the myeloid disease phenotype observed in vivo but enables us to study previously unknown disease pathology. This is an example how iPSC technology enhances our understanding of a rare disease that has thus far been limited by the availability of study material.