Game of clones: the genomic evolution of severe congenital neutropenia

Severe congenital neutropenia (SCN) is a genetically heterogeneous condition of bone marrow failure usually diagnosed in early childhood and characterized by a chronic and severe shortage of neutrophils. It is now well-established that mutations in HAX1 and ELANE (and more rarely in other genes) are the genetic cause of SCN. In contrast, it has remained unclear how these mutations affect neutrophil development. Innovative models based on induced pluripotent stem cell technology are being explored to address this issue. These days, most SCN patients receive life-long treatment with granulocyte colony-stimulating factor (G-CSF, CSF3). CSF3 therapy has greatly improved the life expectancy of SCN patients, but also unveiled a high frequency of progression toward myelodysplastic syndrome (MDS) and therapy refractory acute myeloid leukemia (AML). Expansion of hematopoietic clones with acquired mutations in the gene encoding the G-CSF receptor (CSF3R) is regularly seen in SCN patients and AML usually descends from one of these CSF3R mutant clones. These findings raised the questions how CSF3R mutations affect CSF3 responses of myeloid progenitors, how they contribute to the pre-leukemic state of SCN, and which additional events are responsible for progression to leukemia. The vast (sub)clonal heterogeneity of AML and the presence of AML-associated mutations in normally aged hematopoietic clones make it often difficult to determine which mutations are responsible for the leukemic process. Leukemia predisposition syndromes such as SCN are unique disease models to identify the sequential acquisition of these mutations and to interrogate how they contribute to clonal selection and leukemic evolution.