Programmed cell death (apoptosis) plays an important role in normal erythropoiesis (Figure 2.8), helping to regulate the accumulation of erythroid precursors to match the need for new mature red cells. Excess erythroid precursors are removed by apoptosis, and at least two pathways seem to be involved. First, it appears that late BFU-E, CFU-E and pronormoblasts may all require continuous signalling via the erythropoietin receptor, which is highly expressed on the surface of these cells, to prevent apoptosis. In the absence of Epo, these cells rapidly undergo programmed cell death in culture. It has been shown that, in part, this reflects a need for signals from the EpoR, via the JAK2-STAT 5 pathway, to induce or stabilize expression of the anti-apoptotic protein Bcl-XL.
Apoptosis of erythroid precursors may also occur as a result of activation of the Fas receptor (FasR, known as CD95) that is present on both early and late erythroid precursors, although its activating ligand (FasL, known as CD95L) appears only on late erythroblasts. Binding of FasL to FasR activates proteolytic caspases that cleave intracellular proteins, possibly including the erythroid transcription factor GATA-1, with subsequent loss of Bcl-XL. This regulation of erythropoiesis by negative feedback is thought to take place in the erythropoietic islands of the bone marrow, where the number of mature erythroblasts may control the expansion and differentiation of their less mature precursors.
As well as extracellular anti-apoptotic signals, erythroblasts also use internal programmes to ensure their own survival. The transcription factor GATA-1 is essential for maturation of erythroblasts; the absence of GATA-1 leads to apoptosis and a block in maturation. Some of the target genes regulated by GATA-1 are likely to be important for cell survival. Although many of the targets are unknown, it is clear that GATA-1 strongly induces expression of Bcl-XL and may therefore cooperate with EpoR signalling. In this way, Epo signalling, Fas-mediated signalling and GATA-1 converge on Bcl-XL, which represents a key target of the erythroid cell survival programme.
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