Blood, 15 December 2001, Vol. 98, No. 13, pp. 3504-3504
Some signals are more equal than others
We take it for granted that administering growth factors such
as EPO or GM-CSF causes a selective increase in patients' hematocrit or granulocyte/monocyte counts, respectively. These selective effects
of cytokines are in part due to lineage-restricted expression of their
cognate receptors on late hematopoietic progenitors. But since multiple
cytokine receptors are coexpressed on early committed progenitors and
stem cells, it is conceivable that these cells can distinguish among
specific incoming signals originating from different receptors and
translate this information into activation of differentiation programs.
If so, we would of course like to break the code in which this
information is encrypted.
Although very attractive, the concept of specific instructive signaling
by cytokine receptors has remained controversial. Hisakawa and
colleagues (page 3618) provide evidence largely in support of an
alternative permissive model. They examined the effects of a functional
human GM-CSF receptor (hGM-CSFR) ectopically expressed on erythroid
progenitors of transgenic mice. Due to species specificity, activation
of the transgenic hGM-CSFR is entirely dependent on exogenous human
ligand. Furthermore, to exclude the possibility of cross-talk with the
endogenous mouse EPO receptor (EPOR), hGM-CSFR mice were
crossed with EPOR knockout mice, and fetal
liver cells deficient for EPOR but expressing the
hGM-CSFR transgene were derived. Under these stringent
conditions, hGM-CSF promoted fully differentiated CFU-Es and BFU-Es in
vitro. Furthermore, increased expression of the same adult hemoglobins as in EPO-treated wild-type control cells was observed. These results
argue that the EPO and hGM-CSF signals are equal and interchangeable. But detailed analysis of yolk sac cells at embryonic day 8 revealed subtle differences: only hGM-CSF was able to induce expression of adult
hemoglobins in primitive erythropoietic cells, while both receptors
promoted erythroid-colony formation. Thus specific signaling
information may be detectable only within a particular cellular
context, and hence both the instructive and permissive models may be
partially correct. The next question is, What are the molecular
features defining the cellular context?
Radek C. Skoda
German Cancer Research Center
