Congenital neutropenia (CN) is a heterogeneous group of disorders, characterized by an absolute neutrophil count (ANC) of less than 500 cells per mm3 from birth on and a predisposition of the patients to recurrent and partial life threatening bacterial and fungal infections as a consequence thereof. CN is associated with an exclusive deficiency in neutrophil development. It usually presents early in infancy during the first year of life, and its infectious complications include cellulitis, perirectal abscesses, pneumonitis, peritonitis, stomatitis, and meningitis due to the extremely low ANC (< 200 cells mm 3). The numbers of circulating monocytes and eosinophils are often increased. However, there is a cumulative incidence of 21% for a malignant transformation in CN after 10 years on G-CSF. Point mutations in the gene for the G-CSF receptor CSF3R have been implicated in the progression of CN to leukemia: In 42% out of 219 CN patients tested so far we could demonstrate acquired nonsense mutations in the CSF3R gene. However, in the subpopulation of patients who have developed leukemia 78% are revealing CSF3R mutations. To clarify the involvement of CSF3R mutations in the process of malignant transformation it is important to know at which stage of hematopoietic development these mutations emerge. Therefore we analyzed single cells of flow cytometrically sorted subpopulations of hematopoietic progenitors and mature hematopoietic cells from bone marrow and peripheral blood of 4 CN patients for the existence of CSF3R mutations. The different cell populations reflect the different lineages of hematopoietic development (CD33+, CD34+, CD14+, CD3+, CD19+, CD16+). Two patients characterized by the occurrence of multiple mutations were screened before any signs of malignant transformation and two patients were analyzed at time of secondary AML. Mutated cells were found in all analyzed populations including lymphocytes. However, in the CD34+ cells, eosinphil granulocytes and in the lymphocytic cells the frequency was much lower than in the G-CSFR expressing monocytes and neutrophil granulocytes. These results suggest an in vivo growth advantage of cells expressing a truncated G-CSFR confirming in vitro results with transfected cell lines and underlines the significance of CSF3R mutations in leukemogenesis in CN patients.

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