SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma.

TitleSHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma.
Publication TypeJournal Article
Year of Publication2022
AuthorsWilke, AC, Doebele, C, Zindel, A, Lee, KSeok, Rieke, SA, Ceribelli, M, Comoglio, F, Phelan, JD, Wang, JQ, Pikman, Y, Jahn, D, Häupl, B, Schneider, C, Scheich, S, Tosto, FA, Bohnenberger, H, Stauder, P, Schnütgen, F, Slabicki, M, Coulibaly, ZA, Wolf, S, Bojarczuk, K, Chapuy, B, Brandts, CH, Stroebel, P, Lewis, CA, Engelke, M, Xu, X, Kim, H, Dang, THung, Schmitz, R, Hodson, DJ, Stegmaier, K, Urlaub, H, Serve, H, Schmitt, CA, Kreuz, F, Knittel, G, Rabinowitz, JD, Reinhardt, HChristian, Heiden, MGVander, Thomas, C, Staudt, LM, Zenz, T, Oellerich, T
JournalBlood
Volume139
Issue4
Pagination538-553
Date Published2022 01 27
ISSN1528-0020
KeywordsAnimals, Basic Helix-Loop-Helix Transcription Factors, Burkitt Lymphoma, Cell Line, Tumor, Cell Survival, Drug Discovery, Formates, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Glycine, Glycine Hydroxymethyltransferase, Humans, Mice, Molecular Targeted Therapy, Proteolysis
Abstract

<p>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.</p>

DOI10.1182/blood.2021012081
Alternate JournalBlood
PubMed ID34624079
PubMed Central IDPMC8938936
Grant ListK08 CA222684 / CA / NCI NIH HHS / United States
R35 CA242379 / CA / NCI NIH HHS / United States