|
|
Blood, 15 January 2006, Vol. 107, No. 2, pp. 418-419.
 Previous Article | Table of Contents | Next Article 
HEMATOPOIESIS
Comment on Mirandola et al, page 508
Closing the TRAIL to the DISC
Robert T. Means, Jr
VA MEDICAL CENTER; THE UNIVERSITY OF KENTUCKY MARKEY CANCER CENTER
Sensitivity of erythroid progenitors to TRAIL-induced apoptosis is limited to a period initiated by TRAIL receptor expression and terminated by PKC 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.
View larger version (53K):
[in this window]
[in a new window]
|
Proposed scheme of the period of sensitivity to TRAIL ("TRAIL window") along human erythroid differentiation and the role of PKC in the downstream intracellular signaling pathway. See the complete figure in the article beginning on page 508.
|
|
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 PKC, 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 PKC 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 
References
- Koury MJ, Bondurant MC. Erythropoietin retards DNA breakdown and prevents programmed cell death in erythroid progenitor cells. Science. 1990;248: 378-381.[Abstract/Free Full Text]
- MacFarlane M. TRAIL-induced signalling and apoptosis. Toxicol Lett. 2003;139: 89-97.[CrossRef][Medline]
[Order article via Infotrieve]
- Zamai L, Secchiero P, Pierpaoli S, et al. TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis. Blood. 2000;95: 3716-3724.[Abstract/Free Full Text]
- Silvestris F, Cafforio P, Tucci M, Dammacco F. Negative regulation of erythroblast maturation by Fas-L(+)/TRAIL(+) highly malignant plasma cells: a major pathogenetic mechanism of anemia in multiple myeloma. Blood. 2002;99: 1305-1313.[Abstract/Free Full Text]
- Zang DY, Goodwin RG, Loken MR, Bryant E, Deeg HJ. Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and its receptors in myelodysplastic syndrome: effects on in vitro hemopoiesis. Blood. 2001;98: 3058-3065.[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
PKC controls protection against TRAIL in erythroid progenitors
- Prisco Mirandola, Giuliana Gobbi, Cristina Ponti, Ivonne Sponzilli, Lucio Cocco, and Marco Vitale
Blood 2006 107: 508-513.
[Abstract]
[Full Text]
[PDF]
|
|
