Researchers at UCLA have identified a protein, IGF2BP3, that connects two key processes in leukemia cells: metabolism and RNA modification. Their study, published in Cell Reports, shows that IGF2BP3 alters how leukemia cells break down sugar by favoring glycolysis—a rapid but inefficient energy pathway—while also changing RNA modifications to help the cancer cells survive and multiply.
“We expected IGF2BP3 might control RNA, but what we weren’t expecting was how strongly it also reshaped metabolism,” said Rao, professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA and senior author of the study. “That connection hadn’t been seen before and could be critical to how cancer cells gain their advantage. By uncovering this link, we now have a clearer picture of how leukemia sustains itself. If we can block this rewiring, we might be able to cut off both the energy supply and the survival signals cancer cells rely on.”
Rao’s team has studied IGF2BP3 for nearly ten years. They found that while this family of RNA-binding proteins is usually active only during early human development, IGF2BP3 becomes reactivated in certain cancers such as leukemia, brain tumors, sarcomas, and breast cancers. Previous research indicated that IGF2BP3 is necessary for an aggressive subtype of pediatric acute lymphoblastic leukemia; mice lacking this protein resisted developing leukemia without other health problems.
To examine IGF2BP3’s influence on cellular processes, researchers used Seahorse assays to measure how leukemia cells consume oxygen and produce acid. They observed that removing IGF2BP3 sharply reduced glycolysis in these cells. Additional experiments showed that without IGF2BP3, levels of S-adenosyl methionine (SAM)—a molecule needed for adding chemical tags to RNA—dropped significantly. This led to fewer RNA methylation marks, suggesting a feedback loop between metabolism and gene regulation controlled by IGF2BP3.
In engineered mice missing the gene for IGF2BP3, reintroducing the human version restored changes in metabolism and RNA regulation. “These experiments revealed a chain reaction,” said Sharma, a postdoctoral scholar in Rao’s lab. “When we removed IGF2BP3, it didn’t just change how cells used energy. It also disrupted their chemical balance and the way their RNA was regulated. That’s how we realized IGF2BP3 links metabolism and RNA control in leukemia.”
The results suggest that leukemia cells use less efficient metabolic pathways not for more energy but to create building blocks and RNA modifications needed for survival. “In a way, IGF2BP3 is a master planner,” Sharma explained. “It rewires both energy use and RNA control to keep leukemia cells growing where normal cells wouldn’t.”
While the research focused on leukemia models, Rao believes similar mechanisms may occur in other types of cancer: “While leukemia is the model where we’re seeing this most clearly, the broader message is that cancer cells across the board may be using similar strategies,” said Rao, who is a member of the UCLA Health Jonsson Comprehensive Cancer Center. “This means the insights from our research could eventually help us design therapies that target not only leukemia but also other cancers that exploit the same pathways.”
The team suggests high levels of IGF2BP3 could serve as biomarkers to identify cancers responsive to treatments disrupting either RNA modifications or SAM production. The laboratory is currently testing small molecules designed to block IGF2BP3 activity.
The study included contributors from both UCLA and UC Santa Cruz and received funding from organizations including the National Institutes of Health, The California Institute of Regenerative Medicine, and UCLA Health Jonsson Comprehensive Cancer Center.
