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Stimulating Cell Proliferation Through the Pharmacologic Activation
of c-kit
Liqing Jin,
Haruhiko Asano, and
C. Anthony Blau
From the Department of Medicine, Division of Hematology, University
of Washington, Seattle.
Previous studies have shown that expression of a membrane targeted
chimeric protein containing the erythropoietin receptor (EpoR)
cytoplasmic domain fused to the FK506-binding peptide FKBP12 allowed
Ba/F3 cells to be rescued from interleukin-3 (IL-3) deprivation using a
dimeric form of FK506, called FK1012. In this report, a similar
approach is applied to the c-kit receptor. Expression of a
membrane targeted fusion protein containing the c-kit receptor linked to one or more copies of FKBP12 allowed Ba/F3 cells to be
switched from IL-3 dependence to FK1012-dependence. Similar results
were obtained using an alternative dimerizer of FKBP12 domains called
AP1510. Pharmacologic dimerization of chimeric proteins containing only
a single FKBP12 domain confirmed that receptor dimerization is
sufficient for proliferative signaling. Interestingly, while the
proliferative effects of both FK1012 and AP1510 were reversible,
FK1012-driven proliferation persisted for several days after drug
withdrawal. Furthermore, much higher concentrations of FK506 were
required to inhibit FK1012-mediated proliferation than were required to
inhibit AP1510-mediated proliferation. The persistence of FK1012's
effect appeared to be specific to clones expressing
c-kit-containing fusion proteins. These results suggest that
pharmacologically-responsive fusion proteins containing c-kit
may be useful for specifically and reversibly expanding genetically
modified hematopoietic cell populations.
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 890-897
© 1998 by The American Society of Hematology.
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