Wednesday December 15 2010
The study sheds light on how some types of leukaemia develop
Scientists have discovered how to “switch off faulty stem cells” that can lead to leukaemia, The Daily Telegraph has reported.
The research found that blocking the action of a protein called beta catenin in mice could make certain types of cancerous leukaemia stem cells revert to a pre-cancerous stage. The stem cells also became more susceptible to certain chemotherapy drug treatments. When the researchers suppressed beta catenin in human leukaemia cells they found it could slow their division only if they carried an abnormal form of a gene called MLL, which is associated with certain forms of the disease, including one known as acute myeloid leukaemia. This suggests the results may only apply to cases of leukaemia that involve the abnormal MLL gene.
This well-conducted research provides further insight into leukaemia stem cells, and has identified a protein that could be a good target for new anti-leukaemia drugs. This type of biological research is essential for understanding how cancer develops and identifying ways in which it might be treated.
Where did the story come from?
The study was carried out by researchers from King’s College London and other research centres in the UK. It was funded by the Association for International Cancer Research, Cancer Research UK and the Kay Kendall Leukaemia Fund. The study was published in the peer-reviewed journal Cancer Cell.
The Daily Telegraph provides an accurate report of this study.
What kind of research was this?
This was a laboratory and animal study that aimed to improve understanding of which specific molecular pathways play a role in the formation of leukaemia stem cells. These cells have an unlimited ability to divide and produce new cancerous cells, and are believed possibly to be resistant to chemotherapy drugs. These cells may, therefore, play a key role in the cancer’s ability to maintain itself in the body.
The researchers hope that improving their understanding of how these cells develop may help them to design more effective cancer drugs.
What did the research involve?
The researchers started by looking at what factors trigger the development of pre-leukaemia stem cells (pre-LSCs) into leukaemia stem cells (LSCs).
To do this they used mouse bone marrow stem cells that had been genetically engineered to carry an abnormal form of the Mixed Lineage Leukaemia (MLL) gene, which is found in some cases of acute myeloid leukaemia (AML), as well as some other leukaemias. This abnormal form of the gene can cause the normal mouse bone marrow stem cells that make blood to convert into pre-LSCs. These pre-LSCs may then gain further genetic mutations, causing them to become LSCs, which can, in turn, produce leukaemic cells.
If mice are injected with pre-LSCs they can develop leukaemia, but it will take a long time. However, if mice are injected with LSCs they will develop leukaemia in a short space of time. The researchers used these different properties as a way of identifying whether the mice had received pre-LSCs or LSCs.
The researchers carried out various experiments looking at which genes were switched on in pre-LSCs and LSCs carrying the abnormal MLL gene. They were specifically looking for genes that were more active in LSCs than pre-LSCs, as these genes could be essential to the development and functioning of the LSCs. Once they had identified such a gene, they looked at the effect of suppressing it in LSCs. They also looked at the effect of removing this gene from pre-LSCs carrying the abnormal MLL gene.
The researchers also took human MLL leukaemia cells that had been growing in the laboratory and looked at the effect of reducing the activity of a gene called beta catenin, which they had identified through their earlier steps. They also tried reducing the action of the gene in similar cells taken directly from patients with acute myeloid leukaemia, and in human cord blood stem cells into which the MLL gene had been introduced.
What were the basic results?
The researchers found that the gene encoding the beta catenin protein was activated during the development of leukaemia stem cells (LSCs) in mice. If the researchers suppressed the activity of this gene, the LSCs reverted to having pre-LSC characteristics.
Injecting mice with pre-LSCs carrying the abnormal MLL gene usually causes them to develop leukaemia, but if these pre-LSCs were first genetically engineered to lack the beta catenin gene, they did not cause the mice to develop leukaemia.
The researchers then took LSCs carrying the abnormal MLL gene that had become resistant to a certain family of drugs called GSK3 inhibitors. Suppressing the beta catenin gene made these cells susceptible to the GSK3 inhibitors.
In human leukaemia cells carrying the MLL gene, suppressing the activity of the beta catenin gene reduced the ability of the cells to divide and form colonies of cells. Suppressing the activity of the beta catenin gene in human leukaemia cells not carrying the MLL gene did not have this effect.
How did the researchers interpret the results?
The researchers conclude that their study has identified previously unknown functions of the beta catenin protein in the formation of leukaemia stem cells carrying the MLL gene, and in their drug resistance. They say that beta catenin is a potential target for drugs to treat cases of acute myeloid leukaemia that are associated with the MLL gene.
This thorough research has used mouse models and human cells to identify a role for the beta catenin protein in some types of leukaemia stem cells. The stem cells studied in this research carried an abnormal form of a gene called MLL, which is associated with a proportion of cases of certain types of leukaemia, such as acute myeloid leukaemia (AML). Initial results in human cells in this study suggest that beta catenin may not play the same role in cells not carrying the abnormal MLL gene as in those that do carry this abnormal gene. Further research would be needed to confirm this.
This research provides further insight into leukaemia stem cells, and has identified a protein that could potentially be a good target for new anti-leukaemia drugs. This study typifies the kind of biological research that is essential for understanding how cancer develops and identifying ways in which it might be treated.