Year: 2021
Type: article
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.
Source: Blood
Authors: Anne C. Wilke, Carmen Doebele, Alena Zindel, Kwang Seok Lee, Sara A. Rieke, Michele Ceribelli, Federico Comoglio, James D. Phelan, James Q. Wang, Yana Pikman, Dominique Jahn, Björn Häupl, Constanze Schneider, Sebastian Scheich, Frances A. Tosto, Hanibal Bohnenberger, Philipp Stauder, Frank Schnütgen, Mikolaj Slabicki, Zana A. Coulibaly, Sebastian Wolf, Kamil Bojarczuk, Björn Chapuy, Christian H. Brandts, Philipp Stroebel, Caroline A. Lewis, Michael Engelke, Xincheng Xu, Hahn Kim, Thanh Hung Dang, Roland Schmitz, Daniel J. Hodson, Kimberly Stegmaier, Henning Urlaub, Hubert Serve, Clemens A. Schmitt, Fernando Kreuz, Gero Knittel, Joshua D. Rabinowitz, Hans Christian Reinhardt, Matthew G. Vander Heiden, Craig Thomas, Louis M. Staudt, Thorsten Zenz, Thomas Oellerich
Institutions: Goethe University Frankfurt, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung, National Center for Tumor Diseases, National Institutes of Health, National Center for Advancing Translational Sciences, National Cancer Institute, Boston Children's Hospital, Dana-Farber Cancer Institute, Frankfurt Cancer Institute, Universitätsmedizin Göttingen, Instytut Hematologii i Transfuzjologi, University of Göttingen, Whitehead Institute for Biomedical Research, Princeton University, Justus-Liebig-Universität Gießen, Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Max Planck Institute for Biophysical Chemistry, Johannes Kepler University of Linz, Max Delbrück Center, Kepler Universitätsklinikum, Charité – Universitätsmedizin Berlin, University of Cologne, University Hospital Cologne, Essen University Hospital, Stiftung Universitätsmedizin Essen, Massachusetts Institute of Technology, University of Zurich, University Hospital Zurich
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Howard Hughes Medical Institute, Deutsches Krebsforschungszentrum, Cancer Research UK, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutsche Krebshilfe, Stand Up To Cancer, Ludwig Center at Harvard, Medical Research Council, National Cancer Institute, Hyundai Hope On Wheels
Awards: G182594153, G1968525704, G3455332728, G379299795, G5290293035, Targeting mitochondrial one carbon folate metabolism for novel T-cell acute lymphoblastic leukemia therapy, G579307425, G588085880, G5905007886, G5987310695, Verbundprojekt: Systemische Analyse von Modulatoren der onkogenen Signalübertragung - SMOOSE - Anteil Universität Köln, G6096521174, G6831373058, SFB 1177: Molekulare und funktionale Charakterisierung der selektiven Autophagie, e:Med-Modul-II-Verbundprojekt: SeneSys (for iLymTx) - Seneszenz-basierte systemmedizinische Stratifikation zur individualisierten Lymphomtherapie - Teilprojekt A, Cancer Center Support (Core) Grant, Understanding the role of metabolism in cancer
OpenAlex ID: W3204487665