IGF2BP3 redirects glycolytic flux to promote one-carbon metabolism and RNA methylation

Gunjan Sharma¹, Martin Gutierrez², Anthony E Jones³, Shruti Kapoor², Amit Kumar Jaiswal¹, Zachary T Neeb², Amy Rios³, Poornima Dorairaj¹, Michelle L Thaxton¹, Tasha L Lin⁴, Tiffany M Tran⁵, Lyna E S Kabbani², Alexander J Ritter², Georgia M Scherer⁶, Jacob P Sorrentino⁶, Linsey Stiles⁷, Johanna Ten Hoeve⁸, Robert D Damoiseaux³, Neil K Garg⁶, Ajit S Divakaruni³, Jeremy R Sanford⁹, Dinesh S Rao¹⁰

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California, Santa Cruz, Santa Cruz, CA, USA.
³ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California, Santa Cruz, Santa Cruz, CA, USA; Center for Biomolecular Science & Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
¹⁰ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: drao@mednet.ucla.edu.

PMID: 41015030
DOI: 10.1016/j.celrep.2025.116330

IGF2BP3 redirects glycolytic flux to promote one-carbon metabolism and RNA methylation

Gunjan Sharma et al. Cell Rep. 2025.

. 2025 Sep 26:116330.

doi: 10.1016/j.celrep.2025.116330. Online ahead of print.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California, Santa Cruz, Santa Cruz, CA, USA.
³ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California, Santa Cruz, Santa Cruz, CA, USA; Center for Biomolecular Science & Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
¹⁰ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: drao@mednet.ucla.edu.

PMID: 41015030
DOI: 10.1016/j.celrep.2025.116330

Abstract

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.

Keywords: B-acute lymphoblastic leukemia; CP: Metabolism; MLL-rearranged leukemia; RNA-binding protein; epitranscriptomics.

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Conflict of interest statement

Declaration of interests D.S.R. has served as a consultant to AbbVie, a pharmaceutical company that develops and markets drugs for hematologic disorders. D.S.R., N.K.G., G.M.S., J.P.S., R.D.D., M.L.T., and A.K.J. are inventors on a patent application that includes the compound I3IN-002.

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IGF2BP3 redirects glycolytic flux to promote one-carbon metabolism and RNA methylation

Affiliations

IGF2BP3 redirects glycolytic flux to promote one-carbon metabolism and RNA methylation

Authors

Affiliations

Abstract

Conflict of interest statement