Leukemic Mechanism Unmasked

microRNA Loss May Power Malignant Transformation in CLL

Carlo CroceLoss of a particular microRNA in chronic lymphocytic leukemia 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 neighboring tissue.

The findings come from a study led by researchers at the OSUCCC – James, who showed that microRNA-125b (miR-125b) by itself regulates many enzymes and other molecules that allow cells to make building blocks for their growth and proliferation, such as DNA and lipids needed for cell membranes.

The study also showed that miR-125b is often lost in chronic lymphocytic leukemia (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 researchers say the study provides a more comprehensive understanding of how cancer develops and identifies potential targets for CLL drug development.

“Our findings indicate that miR-125b is downregulated in both aggressive and indolent forms of CLL, and that this downregulation is associated with metabolic adaptation to cancer transformation,” says principal investigator and corresponding author Carlo Croce, MD, director of Human Cancer Genetics at Ohio State and a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program.

“By identifying the metabolites that are changed, as we have here, we can propose to use drugs that target them and perhaps control the leukemia,” Croce says.

Scientists have known for some time that, as normal cells become cancerous, different metabolic pathways are switched on and support the enhanced growth and energy needs of malignant cells. This study reveals one way that can happen.

Published in the journal Blood.

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