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Blood, 15 August 2001, Vol. 98, No. 4, pp. 1195-1199
NEOPLASIA
The Kit-activating mutation D816V enhances stem cell
factor-dependent chemotaxis
Marcia L. Taylor,
Jaroslaw Dastych,
Devinder Sehgal,
Magnus Sundstrom,
Gunnar Nilsson,
Cem Akin,
Rose G. Mage, and
Dean D. Metcalfe
From the Laboratory of Allergic Diseases and Laboratory
of Immunology, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, MD; Laboratory of Molecular
Immunology, International Institute of Molecular and Cell Biology,
Warsaw, Poland; and Department of Genetics and Pathology, Uppsala
University, Uppsala, Sweden.
The D816V mutation of c-kit has been detected in
patients with mastocytosis. This mutation leads to constitutive
tyrosine kinase activation of Kit. Because stem cell factor (SCF), the ligand for Kit (CD117+), is a chemoattractant for
CD117+ cells and one feature of mastocytosis is an abnormal
collection of mast cells in tissues derived from
CD34+CD117+ mast cell precursors, the
hypothesis was considered that the D816V mutation would enhance
chemotaxis of these precursor cells. Constructs encoding wild-type Kit
or Kit bearing the D816V mutation were transfected into Jurkat cells,
labeled with Calcein-AM, and migration to SCF assessed in
the presence or absence of tyrosine kinase inhibitors. Chemotaxis to
SCF was enhanced in D816V transfectants compared to wild-type Kit
transfectants (P < .002). Migration of both
transfectants was inhibited by tyrosine kinase inhibitors, although
D816V transfectants were more sensitive. Chemotaxis was next performed
on CD34+CD117+ circulating mast cell precursors
obtained from patients with mastocytosis. Analysis of prechemotaxis and
migrated cells showed that whereas less than 10% in the prechemotaxis
sample had the D816V mutation, 40% to 80% of migrated cells had this
mutation. These results demonstrate that the D816V Kit mutation
enhances chemotaxis of CD117+ cells, offering one
explanation for increased mast cells observed in tissues of patients
with mastocytosis.
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