Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation

W. Brian Dalton, Eric Helmenstine, Noel Walsh, Lukasz P. Gondek, Dhanashree S. Kelkar, Abigail Read, Rachael Natrajan, Eric S. Christenson, Barbara Roman, Samarjit Das, Liang Zhao, Robert D. Leone, Daniel Shinn, Taylor Groginski, Anil K. Madugundu, Arun Patil, Daniel J. Zabransky, Arielle Medford, Justin Lee, Alex J. ColeMarc Rosen, Maya Thakar, Alexander Ambinder, Joshua Donaldson, Amy E. DeZern, Karen Cravero, David Chu, Rafael Madero-Marroquin, Akhilesh Pandey, Paula J. Hurley, Josh Lauring, Ben Ho Park

Research output: Contribution to journalArticle

Abstract

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers.

Original languageEnglish (US)
Pages (from-to)4708-4723
Number of pages16
JournalJournal of Clinical Investigation
Volume129
Issue number11
DOIs
StatePublished - Nov 1 2019

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Brian Dalton, W., Helmenstine, E., Walsh, N., Gondek, L. P., Kelkar, D. S., Read, A., Natrajan, R., Christenson, E. S., Roman, B., Das, S., Zhao, L., Leone, R. D., Shinn, D., Groginski, T., Madugundu, A. K., Patil, A., Zabransky, D. J., Medford, A., Lee, J., ... Park, B. H. (2019). Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation. Journal of Clinical Investigation, 129(11), 4708-4723. https://doi.org/10.1172/JCI125022