Blood, 1 February 2002, Vol. 99, No. 3, pp. 729-729
Neutrophils at the crossroads of cytokine and RA
receptors
Studies on the leukemogenic process have revealed the
implication of at least 2 pathways in the generation of neutrophils, one involving a membrane receptor, GM-CSFR, and the other one, nuclear
receptors of the RAR family. In tissue culture, GM-CSF induces
CD34+Lin
cells to terminal myeloid
differentiation. Kit ligand (or SCF) antagonizes this effect whereas
retinoids enhance it. Furthermore, cells lacking RAR
/RAR
fail to undergo terminal maturation when exposed to GM-CSF or IL-3 in
vitro. It came therefore as a surprise that neither gm-csf
nor RAR gene knock-out disrupts granulopoiesis in
vivo, suggesting redundancy and/or compensatory mechanisms. The
interest in GM-CSF resurfaced with the discovery that leukemic cells in
juvenile chronic myeloid leukemia (JCML) are hypersensitive to GM-CSF,
followed by the demonstration of a genetic interaction between
gm-csf and Nf1, a gene frequently deleted in
JCML. In acute promyelocytic leukemia (APL), the involvement of the
RAR locus in chromosomal translocations with 5 distinct
fusion partners indicates that loss of RAR function is the primary
event in leukemogenesis.
Johnson and colleagues (page 746) have now provided unequivocal
evidence that GM-CSF and IL-3 enhance both ligand-dependent and
ligand-independent transcriptional activity of RA receptors. Moreover,
RA receptor activation is exquisitely dependent on GM-CSFR and IL-3R
signaling and does not occur with activated c-Kit. This induction
correlates with biologic outcome in neutrophil maturation and, together
with the RAR gene knock-outs, suggests a critical role for
RA receptor activation in IL-3 and GM-CSF signaling. Since loss of RAR
function is associated with APL, a colinearity between RAR and
GM-CSF implies that a loss of function of GM-CSF might also be
associated with myeloid leukemia. Paradoxically, GM-CSF signaling is
essential in the development of a myeloproliferative disease in
Nf1/ mice. It is possible that signaling
pathways have different outcomes depending on the context of the cell,
a hypothesis set forth by the authors to explain the differential
sensitivity of myeloid leukemias to ATRA therapy. Regardless of what
future experiments will tell us, Johnson and colleagues unravel here
unsuspected crosstalks between 2 disparate receptor families, bringing
a novel twist to our understanding of signaling pathways.
Trang Hoang
Clinical Research Institute of
Montreal
