Modeling severe congenital neutropenia in induced pluripotent stem cells

Patients with severe congenital neutropenia (SCN) suffer from a severe shortage of neutrophilic granulocytes, leading to life-threatening bacterial infections. The severe neutropenia and infectious episodes can be alleviated by life-long treatment with granulocyte colony-stimulating factor (G-CSF or CSF3). G-CSF therapy has unveiled an increased risk of developing myelodysplastic syndromes or acute myeloid leukemia, which is often preceded by the expansion of myeloid cell clones with somatic mutations in the CSF3 receptor gene (CSF3R). Genetically, SCN is a heterogeneous condition, with over 15 genes identified as causative to the disease. Most commonly, mutations are found in ELANE, the gene encoding neutrophil elastase, leading to autosomal dominant or sporadic forms of SCN. SCN caused by mutations in HAX1 is best known, as this represents the recessive condition originally described as Kostmann disease. Despite our knowledge of the genetic causes of SCN, it remains ill-understood how the mutations cause neutropenia and why they predispose to myeloid malignancies. In this chapter, we will discuss the clinical characteristics of SCN and summarize the properties and limitations of the current in vitro and in vivo models used to study the pathobiology of the disease. Subsequently, we will review the current status of induced pluripotent stem cell models of SCN and discuss their potential and current limitations for elucidating disease mechanisms of neutropenia and leukemic progression, as well as for developing curative therapies.