miRNA loss may power malignant transformation in chronic lymphocytic leukemia
Loss of miR-125b is an early step in CLL development
- Date : 11 Jul 2012
- Topic : Haematologic malignancies
Loss of a particular miRNA in chronic lymphocytic leukaemia (CLL) shuts down normal cell metabolism and turns up alternative mechanisms that enable cancer cells to produce the energy and build the molecules they need to proliferate and invade neighbouring tissue. The findings come from a new study led by researchers at the Ohio State University Comprehensive Cancer Centre – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
miR-125b down-regulated in both aggressive and indolent forms of CLL
The study shows that microRNA-125b (miR-125b) by itself regulates many enzymes and other molecules that allow cells to make building blocks needed for their growth and proliferation such as DNA and lipids needed for cell membranes. It also shows that miR-125b is often lost in CLL, and that the loss is associated with higher rates of glucose metabolism. This is a characteristic of cancer cells called the Warburg effect, and it alters how cancer cells use glucose to generate energy. This finding suggests that loss of miR-125b is an early step in CLL development.
The findings are published in the journal Blood, and provide a more comprehensive understanding of how cancer develops and identifies new potential targets for CLL drug development.
According to principal investigator and corresponding author Dr Carlo Croce, who is director of Ohio State's Human Cancer Genetics program and a member of the OSUCCC – James Molecular Biology and Cancer Genetics program, these findings indicate that miR-125b is down-regulated in both aggressive and indolent forms of CLL, and this down-regulation is associated with metabolic adaptation to cancer transformation. By identifying the metabolites that are changed, the researchers can propose to use drugs that target them and perhaps control the disease.
Scientists have known for some time that, as normal cells become cancer cells, different metabolic pathways are switched on and support the enhanced growth and energy needs that malignant cells require. This study reveals one new way that it can happen.
The power of microRNAs is that they simultaneously control the expression of many genes, usually by suppressing them. The researchers believe that miR-125b is a master regulator of cell metabolism, and that its loss enhances metabolism and leads to a transformed state. As the level of miR-125b goes down in CLL cells, the levels of many of the molecules it controls go up, enabling rapid cell growth.
These molecules, along with miR-125b itself, warrant further investigation as possible targets for new drugs to control CLL progression.
Funding from the USA NIH/National Cancer Institute (grant CA151319) supported this research.
Other researchers involved in this study were from The Ohio State University; Université de Bourgogne, Faculté Gabriel, Dijon, France; and University of California San Diego Cancer Centre.
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