Cancer cells are relentless in their quest to grow and divide, often rewiring their metabolism and modifying RNA to stay one step ahead. Now, researchers at the UCLA Health Jonsson Comprehensive Cancer Center have identified a single protein, IGF2BP3, that links these two processes together in leukemia cells. The protein shifts how cells break down sugar, favoring a fast but inefficient energy pathway, while also altering RNA modifications that help produce the proteins leukemia cells need to survive and multiply.
The discovery, published in Cell Reports, positions IGF2BP3 as a "master switch" in leukemia, linking metabolism and RNA regulation, processes long thought to operate independently. Understanding this connection could pave the way for new therapies aimed at cutting off the energy and survival pathways that cancer cells depend on.
"We expected IGF2BP3 might control RNA, but what we weren't expecting was how strongly it also reshaped metabolism," said Dr. Dinesh 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 and his lab have been studying IGF2BP3 for nearly a decade and found that it is essential for the survival of leukemia cells. The protein belongs to a family of RNA-binding proteins that are normally active only at the earliest stages of human development. After birth, their activity largely shuts down, but in some cancers — including leukemia, brain tumors, sarcomas, and breast cancers — IGF2BP3 switches back on.
The team has previously shown that IGF2BP3 is essential for an especially aggressive subtype of pediatric acute lymphoblastic leukemia. Mice engineered to lack the protein were resistant to developing leukemia, yet remained otherwise healthy, suggesting IGF2BP3 is uniquely tied to cancer biology. The rewiring of cellular metabolism has long been a central focus in cancer research, and Rao's team began to explore whether IGF2BP3 also shapes how leukemia cells process energy.
To understand how IGF2BP3 influences these processes, Rao and his team used a specialized technology called the Seahorse assay, which measures how cells use oxygen and produce acid, essentially putting cells "on a treadmill" to see how they burn energy.
They found when leukemia cells were stripped of IGF2BP3, their preferred energy pathway, glycolysis, dropped sharply. Glycolysis is a quick but wasteful way of breaking down sugar, often favored by cancer cells because it produces the building blocks they need to multiply.
Further experiments traced how sugar was being processed inside the cell. The team discovered that levels of S-adenosyl methionine, or SAM, a critical molecule that donates chemical tags used to modify RNA, fell dramatically without IGF2BP3. As a result, the number of RNA methylation marks also decreased, revealing that IGF2BP3 doesn't just regulate genes, but also rewires metabolism in ways that feed back into RNA control.
As a final step, the researchers used specially engineered mice that lacked the IGF2BP3 gene. When they reintroduced the human version of the protein, the changes in metabolism and RNA regulation returned, confirming IGF2BP3's central role in driving these processes.
"These experiments revealed a chain reaction," said Dr. Gunjan Sharma , a postdoctoral scholar in the Rao laboratory. "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 findings suggest that IGF2BP3 allows leukemia cells to take a less efficient metabolic pathway not because it provides more energy, but because it supplies building blocks and RNA modifications that reinforce cancer cell 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 study focused on leukemia, the researchers believe the implications may extend to many other cancers.
"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 and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA . "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."
High levels of IGF2BP3 could also serve as a biomarker, the researchers noted, helping to identify cancers that may respond to therapies disrupting RNA modifications or SAM production. Rao's lab is now testing small molecules that block IGF2BP3, with the most promising strategies likely pairing these inhibitors with drugs that interfere with cancer metabolism.
Other study authors include Anthony Jones, Amit Jaiswal, Amy Rios, Poornima Dorairaj, Michelle Thaxton, Tasha Lin, Tiffany Tran, Georgia Scherer, Jacob Sorrentino, Linsey Stiles, Johanna Hoeve, Robert Damoiseaux, Neil Garg, and Ajit Divakaruni from UCLA, as well as Martin Gutierrez, Shruti Kapoor, Zachary Neeb, Lyna Kabbani, Alexander Ritter, and Jeremey Sanford from the University of California, Santa Cruz.
The work was supported in part by grants from the National Institutes of Health, The California Institute of Regenerative Medicine and the UCLA Health Jonsson Comprehensive Cancer Center.
