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Cascade transactivation of growth factor receptors in early human
hematopoiesis
U Testa, E Pelosi, M Gabbianelli, C Fossati, S Campisi, G Isacchi and C Peschle
Department of Hematology and Oncology, Istituto Superiore di Sanita, Rome,
Italy.
Highly purified progenitors (including erythroid [BFU-E], granulo-
monocytic [CFU-GM], multipotent [CFU-GEMM] progenitors, as well as
multipotent progenitors with self-renewal capacity [CFU-B]) express
high-affinity growth factor receptors (GFRs), with prevalent interleukin-3
receptors (IL-3Rs) (2,700/cell), a > or = 10-fold lower number of IL-6Rs
(145/cell) and granulocyte-macrophage colony- stimulating factor receptors
(GM-CSFRs) (300/cell), and a barely detectable level of erythropoietin (Ep)
receptors (75/cell). Hematopoietic growth factor (HGF) dosages inducing
peak clonogenetic effects are associated with partial/subtotal occupancy of
the homologous HGF receptor (HGFR). Cross-reactivity between GFRs and
heterologous GFs (including IL-6, IL-3, GM-CSF, Ep, and the kit ligand
[KL]) was explored by competition experiments on purified progenitors with
radiolabeled and excess cold HGFs at +4 degrees C. No cross- reaction was
observed between IL-6R, IL-3R, EpR, and the heterologous GFs, whereas the
GM-CSFR showed cross-reactivity with IL-3 and, to a lesser extent, KL.
Modulation of GFRs was examined after 18 or 40 hours of incubation with
GF(s) at 37 degrees C, followed by ligand-binding assay at 20 degrees C.
IL-6, IL-3, GM-CSF, and Ep induce a marked down- modulation of their own
receptors. Interestingly, each GF induces the transactivation of the R(s)
for the "distal" GF(s): (1) IL-6 induces transactivation of IL-3R, but not
of GM-CSFR/EpR; (2) IL-3 causes a rapid upmodulation of GM-CSFR/EpR ("pure"
progenitors treated with IL-3 show upmodulation of GM-CSFR alpha-chain mRNA
by reverse transcriptase- polymerase chain reaction); whereas (3) GM-CSF
induces the transactivation of the EpR. This chain upmodulation of HGFRs
may underlie the synergistic interactions between the HGFs in clonogenetic
culture. It is emphasized that KL does not induce upmodulation of the other
GFRs. Finally, Ep, GM-CSF, and IL-3 do not modulate the expression of the
"proximal" HGFRs (ie, GM-CSFR/IL-3R/IL-6R, IL-3R/IL- 6R, and IL-6R,
respectively). These results allow insight into the cellular basis of
hematopoiesis, ie, the complex and coordinate interactions between HGFs and
their receptors. They are compatible with a model of cascade
transactivation via upmodulation of GFRs in the initial key steps of
hematopoietic differentiation, whereby the action of each GF enhances the
effect of the distal GF(s) by a multistep chain- potentiation mechanism.
Volume 81,
Issue 6,
pp. 1442-1456,
03/15/1993
Copyright © 1993 by The American Society of Hematology
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