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Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 447-458
RAPID COMMUNICATION
Defective Internalization and Sustained Activation of Truncated
Granulocyte Colony-Stimulating Factor Receptor Found in Severe
Congenital Neutropenia/Acute Myeloid Leukemia
Alister C. Ward,
Yvette M. van Aesch,
Anita M. Schelen, and
Ivo P. Touw
From the Institute of Hematology, Erasmus University, Rotterdam, The
Netherlands; and the Department of Hematology, Dr. Daniel den Hoed
Cancer Center, Rotterdam, The Netherlands.
Acquired mutations truncating the C-terminal domain of the
granulocyte colony-stimulating factor receptor (G-CSF-R)
are found in about 20% of severe congenital neutropenia (SCN)
patients, with this cohort of patients predisposed to acute myeloid
leukemia (AML). In myeloid cells, such mutations act in a
dominant-negative manner leading to hyperproliferation and lack of
differentiation in response to G-CSF. However, why these truncated
receptors are dominant in function over wild-type receptors has
remained unclear. We report that ligand-induced internalization of
truncated G-CSF-R is severely impaired compared with the
wild-type receptor, which results in sustained activation of STAT
proteins. Strikingly, in cells coexpressing both truncated and
wild-type forms, the truncated receptors acted dominantly with regard
to both internalization and sustained activation. Site-directed
mutagenesis of the C-terminus showed that receptor tyrosines in this
region were dispensable for internalization, whereas a
di-leucine-containing motif in Box B3 played some role. However, loss
of the di-leucine motif was not the critical determinant of the
sustained activation status of truncated receptors. These data suggest
that defective internalization, leading to extended receptor
activation, is a major cause of the dominant hyperproliferative effect
of truncated G-CSF receptors, which is only partially due to the loss
of a di-leucine motif present in the Box B3 region of the full-length
receptor.
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