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J. Exp. Med.,
Volume 189, Number 4, February 15, 1999 683-692
By
From the Institute of Hematology, Daniel den Hoed Cancer Center and Erasmus University
Rotterdam, 3000 DR Rotterdam, The Netherlands
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-
715) 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-715 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.
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