Blood, 15 July 2001, Vol. 98, No. 2, pp. 255-256
RCAS1, physiologic or pathologic mediator of apoptosis
In a normal person, the number of circulating erythrocytes
remains within an extremely narrow range, despite a turnover of about
1%, or 200 billion cells, per day. Erythrocyte production is tightly
regulated by the plasma erythropoietin (EPO) level, which in turn is
controlled by oxygen delivery to the kidneys, where EPO is produced.
EPO is a trophic hormone that prevents the apoptosis of erythropoietic
cells at the stages of erythroid colony-forming units (CFU-Es) and
early erythroblasts. Why the erythroid cells at these stages of
differentiation have a propensity to undergo apoptosis is unknown. An
intrinsic process that leads to apoptosis but is inhibited by the
action of EPO may be activated during these stages of erythroid
differentiation. Alternatively, these erythroid cells may develop
susceptibility to an extracellular proapoptotic molecule. CFU-Es and
early erythroblasts have receptors for 2 such proapoptotic molecules,
FAS ligand and TRAIL, which can be produced by other hematopoietic cells.
Matsushima and colleagues (page 313) report that (1) receptors for the
tumor cell antigen RCAS1 are expressed on erythroid cells at the CFU-E
and early erythroblast stages, (2) RCAS1 induces apoptosis in these
cells, and (3) bone marrow macrophages produce RCAS1. Thus, like FAS
ligand and TRAIL, RCAS1 is produced in bone marrow and can induce
apoptosis in EPO-dependent erythroid cells. Major questions about these
proapoptotic molecules include whether they regulate normal
erythropoiesis as molecular counterbalances to the antiapoptotic
effects of EPO and whether they mediate erythropoietic suppression in
pathological states. RCAS1 production by bone marrow macrophages
suggests that both roles, physiologic counterbalance and pathologic
mediator, are possible. During normal differentiation, erythroblasts
and macrophages have contact in erythroblastic islets, such that one
macrophage producing or displaying RCAS1 could induce apoptosis in
multiple erythroblasts. In anemias due to chronic inflammation or
malignancy, increased numbers or activity of macrophages could lead to
decreased erythropoiesis by iron sequestration, by cytokine
elaboration, and, it appears, by RCAS1-mediated erythroid cell
apoptosis. Determining how RCAS1 and other proapoptotic
molecules influence normal and pathologic erythropoiesis should help
identify mechanisms underlying these chronic anemias.
Mark J. Koury
Vanderbilt University
