What A Stem Cell Wnts
(Mirko von Elstermann)
Wnt signaling is well known for its involvement in development andpathogenesis. Studies by Scheller et al. and by Kirstetter et al. in Nature Immunology now show that transgenic expression of a stable form of ß-catenin blocksdifferentiation of murine HSCs.To elucidate the consequences of conditionally overexpressed wild typeß-catenin in mice, both groups designed a conditional expressionsystem without retroviral or oncogenic components. In both studies,FACS analysis indicated that the differentiation of HSCs was arrestedat early blood cell progenitor stages, leading to fatal anemia in thetransgenic mice. Furthermore, failure of bone marrow engraftment bytransformed HSCs in nude mice showed that the renewal potential of theHSCs was disrupted by ß-catenin overexpression.Using rt-PCR analysis, Kirstetter et al. discovered that the genes responsible for HSC population expansion and myeloid progenitor formation were significantly downregulated. However, the block of erythroid differentiation was due to ectopic PU.1 expression causing GATA-1 downregulation.Scheller et al. in turn showed that transgenic HSCs had increased levels of cyclins E1 and E2 and reduced expression of the CDK inhibitory kinase p21kip/waf, which is essential for maintaining resting HSCs. Thus, the presence of ß-catenin enables HSCs to enter the cell cycle but depletes the stem cell reservoir, resulting in a loss of long-term engraftment capacity.The differentiation blockage of transgenic HSCs shown in both studies is similar to the phenotype of leukemic cells, yet the exhaustion rather than the renewal of the HSC population indicates that Wnt signaling is not sufficient for leukemic transformation.The results of these two studies may allow targeting leukemic cells without disturbing HSCs by altering the Wnt pathway.
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