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 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.
Team leader Dr. 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 (ALL). 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.
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. While the study focused on leukemia, the researchers believe the implications may extend to many other cancers. 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.
This is what also exactly deem professor Palanichamy at the Department of Biochemistry, All India Institute of Medical Sciences, New Delhi. Keeping in mind that RNA methylation is performed by writers (METTL3, METTL14), readers (IGF2BPs) and erasers (ALKBH5, FTO), scientists examined a cohort of 227 pediatric B-ALL patients (152 primary and 75 relapsed) and assessed the expression profiles of m6A machinery genes, including both writers and erasers, as well as the m6A readers IGF2BP RNA-binding proteins. All the three category of proteins were found upregulated in B-ALL patients, both in the primary and relapsed groups, and that the expression of IGF2BP3, METTL3, and FTO genes, independently predicted lower overall survival and event-free survival in primary B-ALL patients.
But Dr. Rao’s team already published preliminary results indicating that a compound developed by them, named I3IN-002, shows consistent cell growth-inhibitory activity, altered cell cycle and increased apoptosis in multiple leukemia cell lines, and is the most potent inhibitor of IGF2BP3 reported to date.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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