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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.

Key Words: neutropenia • severe congenital neutropenia • granulocyte colony-stimulating factor receptor • mutations • acute myeloid leukemia

This work was financed by a grant from the Netherlands Organization for Scientific Research NWO (to M.H.A. Hermans, C. Antonissen, and I.P. Touw), a European Molecular Biology Organization Long-term Fellowship (to A.C. Ward), and grants from the Dutch Cancer Society (to I.P. Touw).

Abbreviations used: AML, acute myeloid leukemia; BM, bone marrow; CAFC, cobblestone area–forming cell; CFC, colony-forming cell; EPO, erythropoietin; SCF, stem cell factor; SCN, severe congenital neutropenia; STAT, signal transducer and activator of transcription.

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This article has been cited by other articles:

• Ward, A. C., van Aesch, Y. M., Gits, J., Schelen, A. M., de Koning, J. P., van Leeuwen, D., Freedman, M. H., Touw, I. P. (1999). Novel Point Mutation in the Extracellular Domain of the Granulocyte Colony-Stimulating Factor (G-Csf) Receptor in a Case of Severe Congenital Neutropenia Hyporesponsive to G-Csf Treatment. JEM 190: 497-508 [Abstract] [Full Text]  

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