2. Academic Validation
  3. SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma

SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma

  • Blood. 2022 Jan 27;139(4):538-553. doi: 10.1182/blood.2021012081.
Anne C Wilke 1,  Carmen Doebele 1 2,  Alena Zindel 1 2,  Kwang Seok Lee 3,  Sara A Rieke 1,  Michele Ceribelli 4,  Federico Comoglio 5,  James D Phelan 6,  James Q Wang 6,  Yana Pikman 7,  Dominique Jahn 1 2,  Björn Häupl 1 2,  Constanze Schneider 1 7 8,  Sebastian Scheich 1 6,  Frances A Tosto 4,  Hanibal Bohnenberger 9,  Philipp Stauder 9,  Frank Schnütgen 1 2 8,  Mikolaj Slabicki 3,  Zana A Coulibaly 6,  Sebastian Wolf 1,  Kamil Bojarczuk 10 11,  Björn Chapuy 10,  Christian H Brandts 1 2 8,  Philipp Stroebel 9,  Caroline A Lewis 12,  Michael Engelke 13,  Xincheng Xu 14 15,  Hahn Kim 15 16,  Thanh Hung Dang 17,  Roland Schmitz 17,  Daniel J Hodson 18,  Kimberly Stegmaier 7,  Henning Urlaub 19 20,  Hubert Serve 1 2 8,  Clemens A Schmitt 2 21 22 23,  Fernando Kreuz 24 25,  Gero Knittel 24 25,  Joshua D Rabinowitz 14 15,  Hans Christian Reinhardt 2 26,  Matthew G Vander Heiden 27 28,  Craig Thomas 4 6,  Louis M Staudt 6,  Thorsten Zenz 3 29,  Thomas Oellerich 1 2 8
Affiliations

Affiliations

  • 1 Department of Medicine II, Department for Hematology/Oncology, Goethe University, Frankfurt, Germany.
  • 2 German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
  • 3 Molecular Therapy in Haematology and Oncology and Department of Translational Oncology, NCT and DKFZ, Heidelberg, Germany.
  • 4 Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD.
  • 5 enGene Statistics GmbH, Basel, Switzerland.
  • 6 Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
  • 7 Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA.
  • 8 Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, Germany.
  • 9 Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
  • 10 Department of Hematology and Oncology, Georg August University, Göttingen, Germany.
  • 11 Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
  • 12 Whitehead Institute for Biomedical Research, Cambridge, MA.
  • 13 Institute of Cellular and Molecular Immunology, Georg August University of Göttingen, Göttingen, Germany.
  • 14 Lewis-Sigler Institute for Integrative Genomics.
  • 15 Department of Chemistry, and.
  • 16 Princeton University Small Molecule Screening Center, Princeton University, Princeton, NJ.
  • 17 Institute for Pathology, Molecular Cytology and Functional Genomics, University Hospital Giessen, Giessen, Germany.
  • 18 Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • 19 Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • 20 Bioanalytics, Georg August University, Göttingen, Germany.
  • 21 Charité-University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Berlin, Germany.
  • 22 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • 23 Department of Hematology and Oncology, Kepler University Hospital, Johannes Kepler University, Linz, Austria.
  • 24 Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, and.
  • 25 Center for Integrated Oncology, University of Cologne, Cologne, Germany.
  • 26 Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany.
  • 27 Koch Institute for Cancer Research at MIT, Cambridge, MA.
  • 28 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and.
  • 29 Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
PMID: 34624079 DOI: 10.1182/blood.2021012081
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.

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