Closing the TRAIL to the DISC

Comment on Mirandola et al, page 508

Sensitivity of erythroid progenitors to TRAIL-induced apoptosis is limited to a period initiated by TRAIL receptor expression and terminated by PKCϵ up-regulation.

In 1990, Koury and Bondurant reported that erythropoietin (EPO) prevents apoptosis of erythroid progenitors, and that this was a major part of its role in erythropoiesis.¹  A large number of subsequent studies have confirmed that apoptosis is a central regulator of hematopoietic differentiation and of the size of the hematopoietic progenitor and stem cell populations. Many hematopoietic growth factors and cytokines exert their effects by activating mediators that either oppose or promote apoptosis, such as Bcl-2 or Fas. However, the response to any particular cytokine is not uniform at all points throughout hematopoiesis: one obvious example is that early erythroid progenitors are less sensitive to EPO than are later progenitors.FIG1 

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a member of the TNF cytokine family that appears to play a key role in the body's normal defenses against neoplasia. TRAIL interacts with specific membrane-spanning receptors, some of which are involved in the induction of apoptosis (TRAIL-R1 and TRAIL-R2, the “death receptors”), while others function as decoys (TRAIL-R3 and TRAIL-R4) and do not result in apoptosis. The differential receptor response is presumably responsible for the relative selectivity of TRAIL effects in different cell lineages. The binding of TRAIL to a death receptor leads to intracellular events culminating in the formation of the “death-inducing signaling complex” (DISC), and subsequent apoptosis.²  While TRAIL does appear to have some selectivity for malignant cells, it has been demonstrated that TRAIL also plays a role as a negative regulator of normal erythropoiesis,³  and may be strongly implicated in the impaired erythropoietic response seen in nonerythroid diseases such as multiple myeloma.⁴ 

In a report in this issue, Mirandola and colleagues have studied the inhibitory effect of TRAIL on erythropoiesis using CD34⁺ cells from healthy donors as well as human erythroleukemic cell lines. The authors find that TRAIL induces apoptosis in primary cells and in cell lines, but that sensitivity to TRAIL starts on day 3 when TRAIL death receptors are first expressed, and decreases around day 7, despite the continuing presence of these receptors. The event that appears to be responsible for the progressive decline in TRAIL sensitivity is EPO-driven up-regulation of PKCϵ, which in turn modulates Bcl-2 levels. The possibility that other antiapoptotic mediators may also be involved was not ruled out. The authors propose that sensitivity to the apoptotic effects of TRAIL is limited to a specific period during the progression of erythroid differentiation (see figure).

In addition to demonstrating yet another aspect of the complex balance that composes erythropoiesis and how EPO remains the primary regulator of that balance, the report by Mirandola and colleagues raises interesting questions as to whether modulation of PKCϵ levels in hematopoietic progenitors may play a role in the management of the cytopenias observed in diseases associated with death receptor activity, such as multiple myeloma⁴  or the myelodysplastic syndromes.⁵  ▪