AK2‐Deficient Mice Recapitulate Impaired Lymphopoiesis of Reticular Dysgenesis Patients, but Also Lack Erythropoiesis

TL;DR

This study shows that mice lacking the AK2 gene mimic some features of a rare human immune disorder but also die from severe anemia due to failed red blood cell development.

Contribution

The study introduces a mouse model of AK2 deficiency that reveals species-specific differences in erythropoiesis and myelopoiesis.

Findings

AK2-deficient mice show impaired T-cell development and atrophic thymus, similar to human RD.

Mice with AK2 deficiency die from severe anemia due to a block in definitive erythropoiesis.

Murine erythroid progenitors lack compensatory kinases for AK2 deficiency, unlike human cells.

Abstract

Reticular dysgenesis (RD) is a rare genetic disorder caused by mutations in the adenylate kinase 2 (AK2) gene. It is characterized by a T−B− severe combined immunodeficiency, agranulocytosis, and sensorineural deafness. We established and characterized a haematopoiesis‐specific conditional Ak2‐knockout mouse model to provide a model system to study the molecular pathophysiology of RD. As expected from the human phenotype of RD, haematopoiesis‐specific AK2‐deficient embryos had a small, atrophic thymus consisting mainly of epithelial cells. No recognizable T‐cell component was observed, but B‐cell lineage precursor cells were present in the foetal liver. The effects of AK2 deficiency on myelopoiesis were less severe in mice than in humans. The absolute numbers of monocytes, macrophages, granulocytes and megakaryocytes in foetal liver as well as colony‐forming precursors were not reduced. In contrast to humans, haematopoiesis‐specific Ak2‐knockout mice exhibit embryonic lethality between E13 and E15 due to severe anaemia caused by an early block in definitive erythropoiesis. Murine erythroid progenitors mainly express AK2 and only low levels of functionally related kinases, which are unable to compensate for AK2 deficiency, in contrast to human erythroid progenitors.

Ak2 deficiency leads to impaired development of T and B cells in mice, corresponding to impaired lymphopoiesis of reticular dysgenesis (AK2 deficiency) in humans. In contrast to the human pathophysiology, Ak2 deficiency is lethal in mice due to severe anaemia, and murine myelopoiesis is less affected.

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