Cytokines such as stem-cell factor (SCF) and erythropoietin (EPO) have a crucial role in haematopoiesis, inducing mitogenic and anti-apoptotic factors. Although the molecular pathways by which these cytokines mediate their effects remain ill defined, a report in The Journal of Experimental Medicine has now shed light on the signalling cascades involved, identifying anamorsin as a novel anti-apoptotic factor induced by cytokines during definitive haematopoiesis.
Shibayama et al. used an interleukin-3 (IL-3)-independent variant of a mouse IL-3-dependent cell line to isolate molecules that conferred resistance to apoptosis induced by IL-3 starvation. cDNA encoding anamorsin — a novel protein with no homology to any known anti-apoptotic molecule — was isolated from cells that survived IL-3 deprivation. The anti-apoptotic effect of this protein was confirmed by the observation that stable expression of anamorsin by the parental cell line and by a second IL-3-dependent cell line conferred resistance to apoptosis after IL-3 withdrawal.
In addition to IL-3, anamorsin expression was induced by other cytokines, including SCF and EPO, indicating that it probably has a general role in mediating the anti-apoptotic effects of cytokine exposure in vitro.
The in vivo significance of this molecule was highlighted by the observation that anamorsin-deficient mice die in late gestation. Anamorsin-deficient embryos were anaemic, having half the number of peripheral red blood cells as littermate controls, and a marked proportion of cells in the fetal liver, which was less than a third of the size of that in anamorsin-sufficient embryos, were apoptotic. Interestingly, the absolute number of haematopoietic stem cells and immature pro-erthyrocytes was normal in the fetal liver of anamorsin-deficient embryos, indicating that anamorsin probably has a role in the late stages of haematopoiesis and terminal differentiation. This was confirmed by the observation that anamorsin-deficient fetal liver cells were severely impaired in their ability to generate myeloid and erythroid colonies when cultured in the presence of the appropriate cytokines.
This study identifies anamorsin as a fundamental anti-apoptotic factor induced by cytokines during haematopoiesis. Future studies will focus on the mechanisms by which the anti-apoptotic effects of anamorsin are mediated, and initial studies by the authors indicating that expression of Bcl-XL and Jak2 is downregulated in the absence of anamorsin should provide a good basis to initiate these investigations.
ORIGINAL RESEARCH PAPER
Shibayama, H. et al. Identification of a cytokine-induced antiapoptotic molecule anamorsin essential for definitive haematopoiesis. J. Exp. Med. 199, 581–592 (2004)
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Honey, K. Death-defying factor identified. Nat Rev Immunol 4, 164 (2004). https://doi.org/10.1038/nri1320
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DOI: https://doi.org/10.1038/nri1320