In recent weeks we have discussed the potential of stem cells in developing new therapies, but stem cells also have a more sinister side. Over the past decade scientists have become increasingly interested in the possibility that in many, perhaps most, cancers there is a small population of cells that are the only tumour cells with the capacity for limitless self-renewal, and that to completely cancer from a patient treatments must target these cancer stem cells (CSCs). Until now it has not been clear how the gene disruptions seen in cancer cells relate to their potential to become cancer stem cells, and how the disrupted gene alters cellular signaling pathways to turn the cells into CSCs.
The BBC reports an exciting development at Stanford University where scientists have discovered that CSCs in acute myeloid leukemia (AML), known as leukemia stem cells (LSCs) bear a striking similarity to embryonic stem cells. To make this discovery the scientists led by Dr Tim Somervaille (1) used a mouse model of AML where the mice were injected with hematopoietic stem cells which had been modified by using a retroviral vector to add a mixed-lineage leukemia (MLL) gene whose activity had been altered by fusion with another gene. MLL is an important regulator of gene function in normal development but when it acts abnormally, for example after a mutation fuses it to another gene, it is associated with leukemia, including some cases of human AML. Dr Somervaille found that the number of LSCs found in the spleen and bone marrow of mice that were injected with cells that had been transformed using the MLL-ENL and MLL-AF9 fusion genes was greater than that found in mice that were injected with cells that had been transformed with other MLL fusion genes. Microarray analysis showed that the LSCs produced by MLL-ENL and MLL-AF9 strongly expressed genes that were characteristic of embryonic stem cells and a poor prognosis in the clinic, whereas these genes were not expressed strongly in cells transformed by MLL fusion genes that did not give rise to high numbers of LSCs. They obtained further evidence to support the role of genes of the embryonic stem cell program by demonstrating that when the action of these genes was blocked the number of LSCs that MLL-ENL cells could produce was greatly reduced.
This work indicates that the prognosis for AML patients may depend on the number of LSCs and on the extent to which a gene disruption such as the MLL fusion genes subverts the normal self-renewal program in hematopoietic so that it resembles that of embryonic stem cells. This is exciting since it was previously believed that the LSCs were thought to be similar to normal hematopoietic stem cells, the adult stem cells that are needed to produce blood cells, and the observation that they are in fact more similar to embryonic stem cells may allow the development of chemotherapy that targets the LSCs while sparing the blood cell producing cells. This is a piece of basic research that helps to explain previous clinical observations and may well influence the design of new cancer therapies for years to come.
1) Somervaille T.C.P. et al. “Hierarchical Maintenance of MLL Myeloid Leukemia Stem Cells Employs a Transcriptional Program Shared with Embryonic Rather Than Adult Stem Cells” Cell Stem Cell, Volume 4, Pages 129-140 (2009) doi:10.1016/j.stem.2008.11.015