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SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma

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 th...

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Main Authors: Wilke, Anne C. (Author) , Döbele, Carmen (Author) , Zindel, Alena (Author) , Lee, Kwang Seok (Author) , Rieke, Sara A. (Author) , Ceribelli, Michele (Author) , Comoglio, Federico (Author) , Phelan, James D. (Author) , Wang, James Q. (Author) , Pikman, Yana (Author) , Jahn, Dominique (Author) , Häupl, Björn (Author) , Schneider, Constanze (Author) , Scheich, Sebastian (Author) , Tosto, Frances A. (Author) , Bohnenberger, Hanibal (Author) , Stauder, Philipp (Author) , Schnütgen, Frank (Author) , Słabicki, Mikołaj (Author) , Coulibaly, Zana A. (Author) , Wolf, Sebastian (Author) , Bojarczuk, Kamil (Author) , Chapuy, Björn (Author) , Brandts, Christian H. (Author) , Stroebel, Philipp (Author) , Lewis, Caroline A. (Author) , Engelke, Michael (Author) , Xu, Xincheng (Author) , Kim, Hahn (Author) , Dang, Thanh Hung (Author) , Schmitz, Roland (Author) , Hodson, Daniel J. (Author) , Stegmaier, Kimberly (Author) , Urlaub, Henning (Author) , Serve, Hubert (Author) , Schmitt, Clemens Alexander (Author) , Kreuz, Fernando (Author) , Knittel, Gero (Author) , Rabinowitz, Joshua D. (Author) , Reinhardt, Hans Christian (Author) , Vander Heiden, Matthew G. (Author) , Thomas, Craig (Author) , Staudt, Louis M. (Author) , Zenz, Thorsten (Author) , Oellerich, Thomas (Author)
Format: Article (Journal)
Language:English
Published: January 27, 2022
In: Blood
Year: 2022, Volume: 139, Issue: 4, Pages: 538-553
ISSN:1528-0020
DOI:10.1182/blood.2021012081
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2021012081
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Author Notes: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

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245 1 0 |a SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma  |c 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 
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520 |a 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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