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SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma

Item Type:Article
Title:SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma
Creators Name:Wilke, A.C. and Doebele, C. and Zindel, A. and Lee, K.S. and Rieke, S.A. and Ceribelli, M. and Comoglio, F. and Phelan, J.D. and Wang, J.Q. and Pikman, Y. and Jahn, D. and Häupl, B. and Schneider, C. and Scheich, S. and Tosto, F.A. and Bohnenberger, H. and Stauder, P. and Schnütgen, F. and Slabicki, M. and Coulibaly, Z.A. and Wolf, S. and Bojarczuk, K. and Chapuy, B. and Brandts, C.H. and Stroebel, P. and Lewis, C.A. and Engelke, M. and Xu, X. and Kim, H. and Dang, T.H. and Schmitz, R. and Hodson, D.J. and Stegmaier, K. and Urlaub, H. and Serve, H. and Schmitt, C.A. and Kreuz, F. and Knittel, G. and Rabinowitz, J.D. and Reinhardt, H.C. and Vander Heiden, M.G. and Thomas, C. and Staudt, L.M. and Zenz, T. and Oellerich, T.
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.
Keywords:Basic Helix-Loop-Helix Transcription Factors, Burkitt Lymphoma, Cell Survival, Drug Discovery, Formates, Gene Knockdown Techniques, Glycine, Glycine Hydroxymethyltransferase, Molecular Targeted Therapy, Neoplastic Gene Expression Regulation, Proteolysis, Tumor Cell Line, Animals, Mice
Source:Blood
ISSN:0006-4971
Publisher:American Society of Hematology
Volume:139
Number:4
Page Range:538-553
Date:27 January 2022
Official Publication:https://doi.org/10.1182/blood.2021012081
PubMed:View item in PubMed

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