ArticleBlood2022
SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma.
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Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34citing papers in PubMed
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Who cites it
34 citing papers in PubMed, 45 citations in OpenAlex.
- SHMT2 deficiency disrupts transcriptional regulation through homocysteine-mediated suppression of histone lactylation in Huntington's disease models.The Journal of clinical investigation · 2026Article
- Serine Hydroxymethyltransferase (SHMT) in biology and disease: molecular mechanisms and therapeutic targeting.Journal of translational medicine · 2026Review
- Tumor suppressor function of SHMT in a Drosophila RasCell death & disease · 2026Article
- SHMT2 inhibition triggers mitochondrial apoptosis to suppress lung adenocarcinoma progression.Journal of translational medicine · 2026Article
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- ID2 Suppresses Multiple Myeloma Cell Proliferation by Repressing the Activity of the Transcription Factor TCF3.Blood cancer discovery · 2026Article
- Short-chain fatty acids in the tumor microenvironment: from molecular mechanisms to cancer therapy.Theranostics · 2026Review
- Amino Acid Metabolic Enzymes in Gastric Cancer: Roles and Mechanisms in Tumorigenesis and Progression.Oncology research · 2026Review
- Amino acids metabolism: a potential target for cancer treatment.Molecular cancer · 2025Review
- Serine metabolism reprogramming in cancer: a multi-tiered regulatory framework.Acta biochimica et biophysica Sinica · 2025Review
- Biphasic control of the B cell transcriptome by mTORC1 and GSK3.Cell reports · 2025Article
- Novel Molecular Insights and Evolution of Less Toxic Therapeutic Strategies in Burkitt Lymphoma.Cancers · 2025Review
- SHMT2 overexpression improves glaucoma by enhancing mitophagy in retinal ganglion cells through promoting the phospho of PINK1.Diagnostic pathology · 2025Article
- Guanine monophosphate synthase-mediated nuclear and mitochondrial communication in the progression of gastric cancer.Translational cancer research · 2025Article
- Hydroxymethyltransferase 2 promotes the development of glioblastoma by mediating WTAP regulation of PTEN N6-methyladenosine modification.Metabolic brain disease · 2025Article
- TFE3 and HIF1α regulates the expression of SHMT2 isoforms via alternative promoter utilization in ovarian cancer cells.Cell death & disease · 2025Article
- Proteogenomic characterization of skull-base chordoma.Nature communications · 2024Article
- SH2 domain-containing inositol 5-phosphatases support the survival of Burkitt lymphoma cells by promoting energy metabolism.Haematologica · 2024Article
- Article
- Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.Nature communications · 2024Article
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Authors and funding
45 authors at 17 institutions in 6 countries.
Anne C WilkeDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.
Carmen DoebeleDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.
Alena ZindelDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.
Kwang Seok LeeMolecular Therapy in Haematology and Oncology and Department of Translational Oncology, NCT and DKFZ, Heidelberg, Germany.ORCID 0000-0001-7682-5736
Sara A RiekeDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.ORCID 0000-0002-2890-1308
Michele CeribelliDivision of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD.
Federico ComoglioenGene Statistics GmbH, Basel, Switzerland.ORCID 0000-0002-8970-6610
James D PhelanLymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
James Q WangLymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Yana PikmanDivision of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA.
Dominique JahnDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.
Björn HäuplDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.
Constanze SchneiderDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.
Sebastian ScheichDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.
Frances A TostoDivision of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD.
Hanibal BohnenbergerInstitute of Pathology, University Medical Center Göttingen, Göttingen, Germany.ORCID 0000-0003-1038-1030
Philipp StauderInstitute of Pathology, University Medical Center Göttingen, Göttingen, Germany.ORCID 0000-0002-3876-6023
Frank SchnütgenDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.ORCID 0000-0002-2426-6685
Mikolaj SlabickiMolecular Therapy in Haematology and Oncology and Department of Translational Oncology, NCT and DKFZ, Heidelberg, Germany.
Zana A CoulibalyLymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Sebastian WolfDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.
Kamil BojarczukDepartment of Hematology and Oncology, Georg August University, Göttingen, Germany.
Björn ChapuyDepartment of Hematology and Oncology, Georg August University, Göttingen, Germany.ORCID 0000-0002-6485-8773
Christian H BrandtsDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.ORCID 0000-0003-1732-2535
Philipp StroebelInstitute of Pathology, University Medical Center Göttingen, Göttingen, Germany.ORCID 0000-0002-8528-8060
Caroline A LewisWhitehead Institute for Biomedical Research, Cambridge, MA.
Michael EngelkeInstitute of Cellular and Molecular Immunology, Georg August University of Göttingen, Göttingen, Germany.
Xincheng XuLewis-Sigler Institute for Integrative Genomics.ORCID 0000-0003-1062-2092
Hahn KimDepartment of Chemistry, and.
Thanh Hung DangInstitute for Pathology, Molecular Cytology and Functional Genomics, University Hospital Giessen, Giessen, Germany.
Roland SchmitzInstitute for Pathology, Molecular Cytology and Functional Genomics, University Hospital Giessen, Giessen, Germany.ORCID 0000-0002-3348-6807
Daniel J HodsonWellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.ORCID 0000-0001-6225-2033
Kimberly StegmaierDivision of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA.
Henning UrlaubBioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Hubert ServeDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.ORCID 0000-0001-8472-5516
Clemens A SchmittGerman Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.ORCID 0000-0002-4731-2226
Fernando KreuzDepartment I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, and.
Gero KnittelDepartment I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, and.ORCID 0000-0001-8395-3701
Joshua D RabinowitzLewis-Sigler Institute for Integrative Genomics.ORCID 0000-0002-1247-4727
Hans Christian ReinhardtGerman Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Matthew G Vander HeidenKoch Institute for Cancer Research at MIT, Cambridge, MA.
Craig ThomasDivision of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD.
Louis M StaudtLymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Thorsten ZenzMolecular Therapy in Haematology and Oncology and Department of Translational Oncology, NCT and DKFZ, Heidelberg, Germany.
Thomas OellerichDepartment of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.ORCID 0000-0001-6570-6125
Goethe University Frankfurt · DENational Institutes of Health · USUniversitätsmedizin Göttingen · DEBoston Children's Hospital · USHeidelberg University · DEInstitute for Integrative and Experimental Genomics · DEUniversity of Cologne · DEUniversity of Göttingen · DEDana-Farber Cancer Institute · USGerman Cancer Research Center · DEInstytut Hematologii i Transfuzjologi · PLJohannes Kepler University of Linz · ATMax Planck Institute for Biophysical Chemistry · DEPrinceton University · USUniversity of Zurich · CHWellcome/MRC Cambridge Stem Cell Institute · GBWhitehead Institute for Biomedical Research · US
Funding
VIRUS PRODUCTION COREP30CA014051 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Kristin A Knouse · 1985 to 2026
$93.9MOncogenic mechanisms and molecular targets in lymphomaZIABC011008 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI STAUDT, LOUIS · 2009 to 2025
$21.0MMolecular diagnosis and outcome prediction in lymphomaZIABC011006 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI STAUDT, LOUIS · 2009 to 2025
$21.0MRNA interference-based screens for molecular targets in cancerZIABC011007 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI STAUDT, LOUIS · 2009 to 2025
$21.0MScientific Cyberinfrastructure Research ProgramZIAES103385 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI WALKER, VICKIE · 2022 to 2025
$17.4MHTS enabled examination of drug combinationsZIATR000047 · NCATS · NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES · PI THOMAS, CRAIG · 2015 to 2025
$7.1MUnderstanding the role of metabolism in cancerR35CA242379 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI VANDER HEIDEN, MATTHEW G. · 2019 to 2025
$5.8MTargeting mitochondrial one carbon folate metabolism for novel T-cell acute lymphoblastic leukemia therapyK08CA222684 · NCI · DANA-FARBER CANCER INST · PI PIKMAN, YANA · 2018 to 2022
$886kMedical Research Council MC_PC_17230NCI NIH HHS K08 CA222684NCI NIH HHS P30 CA014051NCI NIH HHS R35 CA242379
Abstract
Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL. We focused on serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. Inhibition of SHMT2 by either knockdown or pharmacological compounds induced anti-BL effects in vitro and in vivo. Mechanistically, SHMT2 inhibition led to a significant reduction of intracellular glycine and formate levels, which inhibited the mTOR pathway and thereby triggered autophagic degradation of the oncogenic transcription factor TCF3. Consequently, this led to a collapse of tonic BCR signaling, which is controlled by TCF3 and is essential for BL cell survival. In terms of clinical translation, we also identified drugs such as methotrexate that synergized with SHMT inhibitors. Overall, our study has uncovered the dependency landscape in BL, identified and validated SHMT2 as a drug target, and revealed a mechanistic link between SHMT2 and the transcriptional master regulator TCF3, opening up new perspectives for innovative therapies.
Indexed as
AnimalsBasic Helix-Loop-Helix ProteinsBurkitt LymphomaCell Line, TumorCell SurvivalDrug DiscoveryFormatesGene Expression Regulation, NeoplasticGene Knockdown TechniquesGlycineGlycine HydroxymethyltransferaseHumansMiceMolecular Targeted TherapyProteolysisBasic Helix-Loop-Helix ProteinsFormatesformic acidGlycineGlycine HydroxymethyltransferaseSHMT protein, humanTCF3 protein, human
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