Study reveals how a single protein rewires leukemia cells to fuel their growth

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UCLA researchers discover a hidden link between cancer metabolism and RNA regulation, offering potential new targets for therapy

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.

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.
 
IGF2BP3 redirects glycolytic flux to promote one-carbon metabolism and RNA methylation
Gunjan Sharma; Martin Gutierrez; Anthony E Jones; Shruti Kapoor; Amit Kumar Jaiswal; Zachary T Neeb; Amy Rios; Poornima Dorairaj; Michelle L Thaxton; Tasha L Lin; Tiffany M Tran; Lyna Es Kabbani; Alexander J Ritter; Georgia M Scherer; Jacob P Sorrentino; Linsey Stiles; Johanna ten Hoeve; Robert D Damoiseaux; Neil K Garg; Ajit S Divakaruni; Jeremy R Sanford; Dinesh S Rao

Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal RNA-binding protein and a non-canonical reader of N6-methyladenosine (m6A) mRNA modifications, is known to be critical for leukemogenesis.

To understand how the oncogenic function of IGF2BP3 impacts metabolism, we performed metabolic profiling and observed changes in glycolytic flux and one-carbon metabolism, including the biosynthesis of S-adenosyl methionine (SAM), a key substrate for methylation reactions within the cell. Using enhanced crosslinking immunoprecipitation (eCLIP) and polyribosome profiling, we found that IGF2BP3 promotes translation of the regulatory subunit of the methionine adenosyltransferase complex (MAT2B), which is involved in SAM production.

Remarkably, IGF2BP3 promotes and alters the level and pattern of m6A modifications on mRNA. Taken together, these data suggest the intriguing hypothesis that IGF2BP3 rewrites the epitranscriptome in leukemia cells. Furthermore, this work highlights an interconnection between oncogenic metabolism and RNA modifications, suggesting that pervasive gene expression changes necessary for oncogenesis may be perpetuated by post-transcriptional gene regulation.

HIGHLIGHTS
• IGF2BP3 regulates one-carbon metabolism

• IGF2BP3 supports the translation of the MAT2B, a subunit of the MAT2 complex

• Enforced expression of IGF2BP3 promotes m6 A marks on RNA both in vitro and in vivo

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