SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma

Author:

Wilke Anne C.1,Doebele Carmen12,Zindel Alena12,Lee Kwang Seok3ORCID,Rieke Sara A.1ORCID,Ceribelli Michele4,Comoglio Federico5ORCID,Phelan James D.6,Wang James Q.6,Pikman Yana7,Jahn Dominique12,Häupl Björn12,Schneider Constanze178,Scheich Sebastian16,Tosto Frances A.4,Bohnenberger Hanibal9ORCID,Stauder Philipp9ORCID,Schnütgen Frank128ORCID,Slabicki Mikolaj3,Coulibaly Zana A.6,Wolf Sebastian1,Bojarczuk Kamil1011,Chapuy Björn10ORCID,Brandts Christian H.128ORCID,Stroebel Philipp9ORCID,Lewis Caroline A.12,Engelke Michael13,Xu Xincheng1415ORCID,Kim Hahn1516,Dang Thanh Hung17,Schmitz Roland17ORCID,Hodson Daniel J.18ORCID,Stegmaier Kimberly7,Urlaub Henning1920,Serve Hubert128ORCID,Schmitt Clemens A.2212223ORCID,Kreuz Fernando2425,Knittel Gero2425ORCID,Rabinowitz Joshua D.1415ORCID,Reinhardt Hans Christian226,Vander Heiden Matthew G.2728,Thomas Craig46,Staudt Louis M.6,Zenz Thorsten329,Oellerich Thomas128ORCID

Affiliation:

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

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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