Key gene in leukemia discovered
Acute myeloid leukemia (AML) is one of the most common forms of blood cancer among adults and is associated with a low survival rate, and leads to the inhibition of normal blood formation. Now, a research team at Lund University in Sweden has identified one of the genes that is the basis for leukemia stem cells’ survival and multiplication. The study is published in Cell Reports.
AML is the result of acquired genetic changes in the blood-forming stem cells and among other things affects genes that control the cells’ maturation and growth. Although the disease occurs at all ages from childhood onwards, it is more common among the elderly.
“It is the leukemia stem cells in the bone marrow that drive the disease forwards and that is why we want to investigate which genes control these stem cells. By employing special gene scissors, CRISPR, we have been able, using an animal model, to study around 100 genes at the same time. It is the first time we have conducted such a large-scale study”, says Marcus Järås, research team manager at Lund University.
The new method using gene scissors means that the researchers can effectively control which gene is turned off, making it possible to study the gene’s function and thus better understand how diseases arise. The Lund researchers found that the gene CXCR4 is essential for the leukemia stem cells’ survival. When they cut off this gene, the leukemia stem cells could not survive, as they are totally dependent on the protein that the gene produces.
“When we turned off CXCR4 this created oxidative stress and the leukemia stem cells matured into cells with a limited lifetime. Oxidative stress arises due to the waste products formed when oxygen is converted into energy. It is a process that is well regulated in the cell, but when there is an increase in waste products this results in toxicity which leads to the death of the cell”, says Ramprasad Ramakrishnan, first author of the study.
In normal blood formation, the interaction between the proteins CXCL12 and CXCR4 is important for the blood stem cells. In contrast, the research team discovered that CXCL12 is not necessary for the leukemia stem cells, which shows a fundamental difference in how leukemia stem cells and normal blood stem cells are regulated.
“It was surprising that CXCL12 is not significant for the leukemia stem cells. This is something that in the long term can be utilised in the design of new drugs against AML”, concludes Ramprasad Ramakrishnan.
Funding bodies: Swedish Research Council, Swedish Childhood Cancer Fund and Swedish Cancer Society.
Publication: CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia
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CRISPR GENE SCISSORS
The CRISPR gene tool is a breakthrough for gene editing. Compared with earlier techniques the CRISPR gene tool is cheaper, faster and simpler to use, which creates new possibilities to change and replace parts of the genome. In addition to its use as a tool in research, CRISPR has the potential to improve life for many patients who currently live with serious diseases such as genetic disorders.
CRISPR is controlled by an RNA molecule that binds to a specific sequence in the genome. The natural role of CRISPR is acting as a defence in bacteria against a virus by cutting in the genome of the virus. Experimentally, CRISPR can be used as a search-and-replace-function that can both remove and add to DNA. The RNA part controls where the cut is to be made by the complex in the DNA. By modifying RNA, CRISPR can be directed to edit anywhere in the genome.