Comment on Brunet de la Grange et al, page 2998
Roles for the SCL/Tal1 gene in primitive hematopoiesis and adult erythropoiesis have been revealed using various murine knockout models. In this issue, a broader lineage effect for SCL in adult human erythropoiesis was revealed using shRNA expressing lentiviral vectors that lowered rather than obliterated SCL expression in human CD34+ progenitor cells.
In this issue, Brunet de la Grange and colleagues add provocative new data to the ongoing controversy over the role of the stem cell leukemia (SCL; aka TAl1) gene during adult hematopoiesis. SCL was first identified as a translocation partner in a leukemia with both myeloid and lymphoid lineage markers. Murine knock-out studies have clearly revealed that SCL is essential for primitive hematopoiesis, but its exact function in regulating lineage commitment and self-renewal in postnatal stem and progenitor cells is still in dispute. The embryonic lethality of the SCL knock-out model has meant that the study of how SCL functions during definitive (or adult) hematopoiesis has required experimental ingenuity, and the resulting models have produced conflicting results. However, all models have found that SCL is essential for adult erythropoiesis and megakaryopoiesis. Two main points of contention remain: first, whether SCL has any role in regulating the repopulating ability of stem cells,1-3 and second, whether SCL affects lineage commitment decisions unrelated to the erythroid pathway.1,2,4
The paper by Brunet de la Grange et al suggests that SCL acts not only at the level of erythroid commitment, but also at both multipotent and myeloid committed stages of adult hematopoiesis. Lentiviral vectors were used to express SCL-directed shRNA in human CD34+ cells. The resulting decrease in SCL expression caused both a significant loss of lymphomyeloid repopulating potential as well as a block to both erythroid and myeloid production. With the intrinsic limitations of the in vitro and in vivo models that are available to measure human stem cells, it is not possible to make direct comparisons of these data with that from classic murine transplantation assays used to measure murine short- and long-term repopulating stem cells. Nevertheless, the data suggest that, in the case of multipotent (lymphomyeloid) stem cells, SCL regulates the most primitive (long-term repopulating) subset of human cells (revealed in vitro only after 10 weeks in culture and in vivo at 12 weeks after transplantation). In short-term assays, reduction in SCL expression caused a loss of committed myeloid and erythroid progenitors. Lymphopoiesis was not affected in short-term assays, consistent with the rapid down-regulation of SCL upon lymphoid commitment.5 Why then were the effects of manipulating SCL expression more wide ranging than in some previous reports? Species differences do not seem to explain the differences, as similar data were obtained when the authors used the shRNA strategy with murine stem/progenitor cells. One key difference is that with the shRNA strategy, although SCL expression was significantly decreased, it was still detectable at low levels. One might expect that partial inhibition would produce less rather than more of a derangement in hematopoiesis compared with the conditional knock-out models where SCL expression is completely absent. This may represent another example of how the exquisite regulation of hematopoiesis is accomplished by a network of relative levels of multiple transcription factors rather than by individual genes turned on or off in a sequential manner. ▪
