Apoptotic mechanisms in the control of erythropoiesis

Abstract

Erythropoiesis is a complex multistep process encompassing the differentiation of hemopoietic stem cells to mature erythrocytes. The steps involved in this complex differentiation process are numerous and involve first the differentiation to early erythoid progenitors (burst-forming units-erythroid, BFU-E), then to late erythroid progenitors (colony-forming unitserythroid) and finally to morphologically recognizable erythroid precursors. A key event of late stages of erythropoiesis is nuclear condensation, followed by extrusion of the nucleus to produce enucleated reticulocytes and finally mature erythrocytes. During the differentiation process, the cells became progressively sensitive to erythropoietin that controls both the survival and proliferation of erythroid cells.A normal homeostasis of the erythropoietic system requires an appropriate balance between the rate of erythroid cell production and red blood cell destruction. Growing evidences outlined in the present review indicate that apoptotic mechanism play a relevant role in the control of erythropoiesis under physiologic and pathologic conditions. Withdrawal of erythropoietin or stimulation of death receptors such as Fas or TRAIL-Rs leads to activation of a subset of caspases-3, -7 and -8, which then cleave the transcription factors GATA-1 and TAL-1 and trigger apoptosis. In addition, there is evidence that a number of caspases are physiologically activated during erythroid differentiation and are functionally required for erythroid maturation. Several caspase substrates are cleaved in differentiating cells, including the protein acinus whose activation by cleavage is required for chromatin condensation.The studies on normal erythropoiesis have clearly indicated that immature erythroid precursors are sensitive to apoptotic triggering mediated by activation of the intrinsic and extrinsic apoptotic pathways. These apoptotic mechanisms are frequently exacerbated in some pathologic conditions, associated with the development of anemia (ie, thalassemias, multiple myeloma, myelodysplasia, aplastic anemia).The considerable progress in our understanding of the apoptotic mechanisms underlying normal and pathologic erythropoiesis may offer the way to improve the treatment of several pathologic conditions associated with the development of anemia.

Mitochondria in hematopoiesis and hematological diseases

“…At early stages of acquired myelodysplastic syndromes, exacerbation of the physiological pathway to caspase activation in erythroid cells, even in the presence of elevated Epo concentrations, is responsible for a high rate of apoptosis, ineffective erythropoiesis and increased phagocytosis (Raza et al, 1995;Bouscary et al, 1997;Hellstrom-Lindberg et al, 2001;Shetty et al, 2002;Tehranchi et al, 2003;Testa, 2004). Several observations argue for a role of the Fas-L/Fas pathway in this pathogenic event.…”

“…Apoptosis of megaloblastic erythroblasts upon folate or cobalamine deficiency, apoptosis of erythroblasts from patients with b-thalassemia, parvovirus B19 infection or congenital aplastic anemia and anemia from patients with multiple myeloma or rheumatoid arthritis could also be related to amplification of a physiological, mitochondria-mediated, caspase activation associated with erythroid differentiation (Testa, 2004). On the other hand, the thrombopenia observed in myelodysplastic patients was recently shown to be related to a necrosis-like, caspase-3-independent death of megakaryocytes (Houwerzijl et al, 2005).…”

Short-term Toxicity Study of ST-20 (NSC-741804) by Oral Gavage in Sprague-Dawley Rats

“…The anemia is caused by excess, unbalanced alpha globin chains that are toxic to the red blood cell, leading to apoptosis of developing erythroblasts at the polychromatophilic normoblast stage with intramedullary hemolysis (Rund and Rachmilewitz 2005;Perrine 2005;Schrier 1997;Koury, Sawyer, and Brandt 2002;Centis et al 2000;Testa 2004;Mathias et al 2000;Yuan et al 1993;Pootrakul et al 2000;Silva et al 1996). The disease is characterized into two major subtypes based upon severity: betathalassemia major and beta-thalassemia intermedia.…”

Regulatory functions of TRAIL in hematopoietic progenitors: human umbilical cord blood and murine bone marrow transplantation

“…23,28,29 Therefore, TRAIL may serve as a negative regulator of expanding clones in the distal stages of differentiation of all hematopoietic lineages. 13,[17][18][19]30,31 As umbilical cord blood (UCB) becomes an important source of hematopoietic progenitors for transplantation, we evaluated the effect of TRAIL in proximal stages of their activity. We recently showed that the Fas/Fas-ligand interaction transduces trophic signals in early stages of hematopoietic cell engraftment, 32 because the most primitive progenitors are insensitive to Fas-mediated apoptosis.…”