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.