Growth Control of Myeloid Cells 
By contrast, transduction of CSF-IR into imma- 
ture pre-B lymphoid cells not only relieves their 
normal dependence on interleukin-7, but can re- 
program the fate of responding cells, enabling 
them to trans-differentiate to mature macro- 
phages in response to CSF- 1 . Physiologic targets 
of the CSF- 1 R kinase must therefore be expressed 
more ubiquitously than the receptor itself and, 
depending on cell context, can modify genetic 
programs governing both cell proliferation and 
fate. 
Transforming Potential of CSF-IR 
CSF- 1 R is encoded by the FMS proto-oncogene , 
which can be converted by mutation to an onco- 
gene that induces tumor formation. Mutations in 
the extracellular domain of CSF-IR activate the 
receptor kinase in the absence of CSF- 1 , leading 
to sustained, unregulated signals for cell growth. 
By mutagenizing segments of human FMS and 
screening "libraries" of mutated genes for their 
ability to induce cell transformation, we local- 
ized particular subdomains within the CSF- 1 R ex- 
tracellular domain where "activating mutations" 
occur. Postulating that similar genetic alterations 
might contribute to leukemogenesis, we are us- 
ing polymerase chain reaction techniques to as- 
say for the presence of activating mutations in the 
FMS genes of myeloid tumor cells. 
CSF- 1 -Responsive Genes Required 
for Cell Division 
CSF- 1 R regulates genes that collectively govern 
macrophage growth, survival, differentiation, 
and effector functions. When proliferating macro- 
phages complete cell division (mitosis), they 
enter a 10- to 12-hour gap phase (Gl) in their 
cell cycle before synthesis of chromosomal DNA 
is reinitiated (S phase). CSF-1 is required 
throughout Gl for the cells to enter S phase, but 
once they begin to replicate DNA, they can com- 
plete S phase and divide in the absence of the 
growth factor. The requirement for persistent 
CSF- 1 R-mediated signals throughout G 1 implies 
that the expression of growth factor-responsive 
genes is temporally regulated over a relatively 
long period. Conceivably, CSF- 1 -responsive gene 
products synthesized early in Gl feed back to 
modulate receptor-mediated signals, so that the 
genes that commit cells to DNA synthesis are ulti- 
mately induced. 
Genetic data accumulated through studies of 
yeasts indicate that a class of cell cycle genes 
called Gl cyclins might act to prime cells for 
DNA synthesis. We recently isolated genes from 
CSF-1 -stimulated mouse macrophages that have 
predicted structural motifs reminiscent of known 
cyclins and whose expression is regulated in Gl . 
Related genes are expressed in other cell types, 
suggesting the presence of a novel cyclin gene 
family. If we can demonstrate that expression of 
these cyclins governs G 1 progression in mamma- 
lian cells, we may be mechanistically able to link 
early steps in CSF- 1 -mediated signal transduction 
with later events required for DNA synthesis. 
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