biostudies-literature00490Dalton WBBreast Cancer Research FoundationLilly Innovation Fellowship AwardNHLBI NIH HHSSusan G. Komen FoundationU.S. Department of DefenseLadies Auxillary of the Veterans of Foreign WarsNCI NIH HHSAbbVieNIHConquer Cancer FoundationNIGMS NIH HHS4708-4723https://www.ebi.ac.uk/biostudies/studies/S-EPMC6819102biostudies-literatureUnknown129(11)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.The Journal of clinical investigationHotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.PMC6819102R01 CA194024N/AR01 CA214494T32 GM008752SAC170079W81XWH- 17-1-0035K08HL136894K12 CA090625K08 HL136894Das SCravero KLauring JDalton WBAmbinder ALee JPatil ALeone RDZhao LMadugundu AKChu DHelmenstine EDeZern AEPandey AThakar MHurley PJKelkar DSShinn DRosen MZabransky DJMadero-Marroquin RRoman BGroginski TPark BHWalsh NGondek LPCole AJMedford ADonaldson JRead AChristenson ESNatrajan R49falseHotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.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.2019-01-01T00:00:00Z2019 Aug2024-11-08T09:21:45.932Z2020-11-19T10:42:05ZS-EPMC68191023139385610.1172/JCI12502210.1172/jci125022