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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4798-4807
An Activating Mutation in the Kit Receptor Abolishes the Stroma
Requirement for Growth of ELM Erythroleukemia Cells, But Does Not
Prevent Their Differentiation in Response to Erythropoietin
Nick R. Leslie,
Jim O'Prey,
Chris Bartholomew, and
Paul R. Harrison
From the Beatson Institute for Cancer Research, CRC Beatson
Laboratories, Glasgow, Scotland.
We have previously shown that murine ELM erythroleukemia cells can
only be grown in vitro in the presence of a stromal feeder layer, or
alternatively stem cell factor (SCF), without which they differentiate.
When grown in the presence of SCF, ELM cells can still differentiate in
response to erythropoietin (Epo), but growth on stroma prevents this.
We previously isolated a stroma-independent ELM variant, ELM-I-1, that
is also defective in Epo-induced differentiation. We show here that
this variant has an activating mutation in the Kit receptor, converting
aspartic acid 814 to histidine. Expression of the mutant receptor in
stroma-dependent ELM-D cells causes growth factor-independent
proliferation and also gives the cells a selective advantage, in terms
of proliferation rate and clonegenicity, compared with ELM-D cells
grown in optimal amounts of SCF. Expression of the mutant receptor in
ELM-D cells also prevents spontaneous differentiation, but not
differentiation induced by Epo. Analysis of mitogenic signaling
pathways in these cells shows that the mutant receptor induces
constitutive activation of p42/p44 mitogen-activated protein kinases.
It also selectively inhibits the expression of p66Shc but not the
p46/p52 Shc isoforms (as did treatment of ELM cells with SCF), which is
of interest, because p66Shc is known to play an inhibitory role in
growth factor signaling.
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