Single Protein IGF2BP3 Rewires Leukemia Cells to Promote Growth and Survival

Cancer cells continuously adapt their metabolism and modify their RNA to sustain their growth and evade treatments. Recent research from UCLA's Jonsson Comprehensive Cancer Center has identified a pivotal protein, IGF2BP3, that acts as a key regulator connecting these processes specifically in leukemia cells. This protein alters how leukemia cells metabolize sugar by shifting them toward a rapid but less efficient energy pathway known as glycolysis. Additionally, IGF2BP3 influences RNA modifications that are crucial for producing proteins essential for leukemia cell survival and proliferation.

Published in Cell Reports, these findings position IGF2BP3 as a central ‘master switch’ in leukemia, linking cellular metabolism with gene regulation previously thought to operate separately. Understanding this dual role could lead to new therapeutic strategies that target both the energy supply and the RNA-based survival mechanisms of cancer cells.

Dr. Dinesh Rao and his team have studied IGF2BP3 for years, recognizing its importance in maintaining leukemia cell viability. Normally active only during early human development, this protein becomes reactivated in cancers such as leukemia, brain tumors, sarcomas, and breast cancers. Previously, the team demonstrated IGF2BP3's necessity for aggressive pediatric leukemia, with models showing that absence of the protein renders cells resistant to leukemia development, while unaltered cells remain vulnerable, indicating IGF2BP3’s critical role in cancer.

To explore further, researchers employed Seahorse assay technology, which measures cellular energy usage by tracking oxygen consumption and acid production. When leukemia cells were lacking IGF2BP3, their glycolytic activity—how they rapidly break down sugar—was significantly diminished. Detailed analysis revealed that without IGF2BP3, levels of S-adenosyl methionine (SAM), a molecule vital for RNA methylation (a chemical modification), dropped sharply, leading to fewer RNA methylation marks. This highlights how IGF2BP3 not only controls gene expression but also rewires metabolism to support leukemia growth.

Reintroducing the human IGF2BP3 in genetically engineered mice restored metabolic activity and RNA modifications, confirming its central regulatory function. "When we removed IGF2BP3, it caused a chain reaction that disrupted energy use, RNA regulation, and the overall chemical balance essential for leukemia cell survival," explained Dr. Gunjan Sharma.

The study suggests that IGF2BP3 enables leukemia cells to adopt a metabolic pathway that, while inefficient in energy production, provides necessary building blocks and RNA modifications to sustain cancer growth. Dr. Sharma emphasized that IGF2BP3 functions as a master planner, rewiring both energy consumption and RNA regulation to favor leukemia cell proliferation where normal cells cannot thrive.

While focused on leukemia, these findings may have broader implications across multiple cancer types. High levels of IGF2BP3 could serve as biomarkers for cancers susceptible to therapies disrupting RNA modifications or SAM synthesis. Current research is testing small molecules that inhibit IGF2BP3, aiming to combine these with metabolic drugs to effectively combat cancer.

This discovery underscores a novel approach in cancer therapy, targeting the interconnected pathways of metabolism and gene regulation to hinder the survival and growth of leukemia and potentially other cancers.