Growth Control of Myeloid Cells 
Charles J. Sherr, M.D., Ph.D. — Investigator 
Dr. Sherr is also a member of the Department of Tumor Cell Biology at St. Jude Children's Research Hos- 
pital and Adjunct Professor of Biochemistry at the University of Tennessee College of Medicine, Memphis. 
He received his medical degree and his Ph.D. degree in immunology from New York University School of 
Medicine, where he studied with Jonathan Uhr. After a pathology residency at Bellevue Hospital Center, 
New York, he Joined George Todaro's laboratory at the National Cancer Institute, where he began studies 
on retroviral oncogenes. After 10 years on the staff of the NCI, Dr. Sherr relocated to St. Jude Children's 
Research Hospital. 
EACH day humans produce billions of blood 
cells, which enter the circulation from their 
sites of origin in the bone marrow. The majority 
are red cells (erythrocytes) , which transport oxy- 
gen, and the remainder are white cells (leuko- 
cytes), which play a vital role in preventing in- 
fection by bacteria, viruses, and other parasites. 
White cells, unlike the continuously circulating 
red cells, migrate from small blood vessels into 
other organs, where they participate in the im- 
mune and inflammatory reactions that character- 
ize host defense. Different classes of white cells 
carry out specialized functions: macrophages and 
granulocytes ingest and kill microorganisms, 
whereas lymphocytes recognize foreign antigens 
and produce antibodies to combat them. 
To maintain constant numbers of cells in the 
circulation, the process of blood cell develop- 
ment (hematopoiesis) must be subject to exqui- 
sitely sensitive regulatory controls. Diseases af- 
fecting blood cell production include those in 
which insufficient numbers of red and white 
cells enter the circulation (anemias and leuko- 
penias); those in which the numbers of normal 
white cells are increased (leukocytosis, seen in 
systemic infections); and those in which cells are 
abnormal (dysplasias) or cancerous (leukemias) . 
Hematopoiesis is regulated by a group of pro- 
tein growth factors, collectively termed colony- 
stimulating factors (CSFs) or interleukins. These 
polypeptides are produced by resident stromal 
cells in the bone marrow as well as by circulating 
blood cells (the term interleukin literally mean- 
ing between white blood cells) . First recognized 
through their ability to stimulate immature bone 
marrow-derived (myeloid) precursor cells to 
form colonies composed of differentiated blood 
cell elements, CSFs were named for the types of 
colonies they produced. For example, M-CSF (or 
CSF-1) specifically induces macrophage colo- 
nies, G-CSF supports granulocyte development, 
and GM-CSF stimulates the proliferation and mat- 
uration of both cell types. 
CSFs, now produced in previously unobtain- 
able quantities by genetic engineering tech- 
niques, have become part of the clinical arma- 
mentarium and have proved particularly useful in 
reversing certain bone marrow failures and in 
heightening impaired host defenses against 
infection. 
Signal Transduction by the CSF-1 Receptor 
CSF-1 (M-CSF) supports the groMT;h, matura- 
tion, and survival of macrophage precursors in 
the bone marrow and potentiates the effector 
functions of mature macrophages during the in- 
flammatory response. Its diverse physiologic 
actions are mediated through its binding to the 
CSF- 1 receptor (CSF- 1 R) , a cell surface glycopro- 
tein. The receptor consists of an extracellular li- 
gand-binding portion, joined through a single 
membrane-spanning segment to an intracellular 
kinase domain capable of phosphorylating other 
cellular proteins on tyrosine residues. Receptor- 
mediated phosphorylation modifies the biochem- 
ical behavior of several effector proteins, which 
then relay signals to the cell nucleus that effect 
changes in gene expression, DNA synthesis, and 
cell division. 
CSF-1 induces dimerization of its receptor at 
the cell surface, activating CSF- 1 R protein kinase 
activity and leading to the cross-phosphorylation 
of receptor subunits on tyrosine. The autophos- 
phorylation of CSF-IR triggers its association 
with other cellular enzymes, whose biochemical 
activities in signal transduction are modified by 
their binding to the receptor, their phosphoryla- 
tion on tyrosine, or both. Mutant CSF-IR mole- 
cules lacking particular autophosphorylation 
sites are defective in some aspects of signaling 
but not others, suggesting that the combinatorial 
actions of enzymes that associate with the recep- 
tor can in part determine the specificity of the 
CSF-1 response in different cell types. 
CSF- 1 R is normally restricted in its expression 
to macrophages and their precursors; it is not de- 
tected on cells of other hematopoietic lineages. 
However, introduction of the gene encoding 
CSF-IR into cells that depend upon other growth 
factors enables them to respond to CSF- 1 . Expres- 
sion of CSF-IR in immature myeloid cells allows 
CSF-1 to replace their interleukin-3 requirements 
for growth and viability. 
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