Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene

In approximately 20% of cases of severe congenital neutropenia (SCN), mutat ions are found in the gene encoding the granulocyte colony-stimulating fact or receptor (G-CSF-R). These mutations introduce premature stop codons, whi ch result in truncation of 82-98 COOH-terminal amino acids of the receptor. SCN patients who develop secondary myelodysplastic syndrome and acute myel oid leukemia almost invariably acquired a GCSFR mutation, suggesting that t his genetic alteration represents a key step in leukemogenesis. Here we sho w that an equivalent mutation targeted in mice (gcsfr-Delta 715) results in the selective expansion of the G-CSF-responsive progenitor (G-CFC) compart ment in the bone marrow. In addition, in vivo treatment of gcsfr-Delta 715 mice with G-CSF results in increased production of neutrophils leading to a sustained neutrophilia. This hyperproliferative response to G-CSF is accom panied by prolonged activation of signal transducer and activator of transc ription (STAT) complexes and extended cell surface expression of mutant rec eptors due to defective internalization. In view of the continuous G-CSF tr eatment of SCN patients, these data provide insight into why progenitor cel ls expressing truncated receptors clonally expand in vivo, and why these ce lls may be targets for additional genetic events leading to leukemia.