9 research outputs found
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),
mutations are found in the gene encoding the granulocyte
colony-stimulating factor receptor (G-CSF-R). These mutations introduce
premature stop codons, which result in truncation of 82-98 COOH-terminal
amino acids of the receptor. SCN patients who develop secondary
myelodysplastic syndrome and acute myeloid leukemia almost invariably
acquired a GCSFR mutation, suggesting that this genetic alteration
represents a key step in leukemogenesis. Here we show that an equivalent
mutation targeted in mice (gcsfr-Delta715) results in the selective
expansion of the G-CSF- responsive progenitor (G-CFC) compartment in the
bone marrow. In addition, in vivo treatment of gcsfr-Delta715 mice with
G-CSF results in increased production of neutrophils leading to a
sustained neutrophilia. This hyperproliferative response to G-CSF is
accompanied by prolonged activation of signal transducer and activator of
transcription (STAT) complexes and extended cell surface expression of
mutant receptors due to defective internalization. In view of the
continuous G-CSF treatment of SCN patients, these data provide insight
into why progenitor cells expressing truncated receptors clonally expand
in vivo, and why these cells may be targets for additional genetic events
leading to leukemia