SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Wilke Anne C, Doebele Carmen, Zindel Alena, Lee Kwang Seok, Rieke Sara A, Ceribelli Michele, Comoglio Federico, Phelan James D, Wang James Q, Pikman Yana, Jahn Dominique, Häupl Björn, Schneider Constanze, Scheich Sebastian, Tosto Frances A, Bohnenberger Hanibal, Stauder Philipp, Schnütgen Frank, Slabicki Mikolaj, Coulibaly Zana A, Wolf Sebastian, Bojarczuk Kamil, Chapuy Björn, Brandts Christian H, Stroebel Philipp, Lewis Caroline A, Engelke Michael, Xu Xincheng, Kim Hahn, Dang Thanh Hung, Schmitz Roland, Hodson Daniel J, Stegmaier Kimberly, Urlaub Henning, Serve Hubert, Schmitt Clemens A, Kreuz Fernando, Knittel Gero, Rabinowitz Joshua D, Reinhardt Hans Christian, Vander Heiden Matthew G, Thomas Craig, Staudt Louis M, Zenz Thorsten, Oellerich Thomas
Аннотация
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.