TY - JOUR
T1 - SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma
AU - Wilke, Anne C.
AU - Doebele, Carmen
AU - Zindel, Alena
AU - Lee, Kwang Seok
AU - Rieke, Sara A.
AU - Ceribelli, Michele
AU - Comoglio, Federico
AU - Phelan, James D.
AU - Wang, James Q.
AU - Pikman, Yana
AU - Jahn, Dominique
AU - Häupl, Björn
AU - Schneider, Constanze
AU - Scheich, Sebastian
AU - Tosto, Frances A.
AU - Bohnenberger, Hanibal
AU - Stauder, Philipp
AU - Schnütgen, Frank
AU - Slabicki, Mikolaj
AU - Coulibaly, Zana A.
AU - Wolf, Sebastian
AU - Bojarczuk, Kamil
AU - Chapuy, Björn
AU - Brandts, Christian H.
AU - Stroebel, Philipp
AU - Lewis, Caroline A.
AU - Engelke, Michael
AU - Xu, Xincheng
AU - Kim, Hahn
AU - Dang, Thanh Hung
AU - Schmitz, Roland
AU - Hodson, Daniel J.
AU - Stegmaier, Kimberly
AU - Urlaub, Henning
AU - Serve, Hubert
AU - Schmitt, Clemens A.
AU - Kreuz, Fernando
AU - Knittel, Gero
AU - Rabinowitz, Joshua D.
AU - Reinhardt, Hans Christian
AU - Vander Heiden, Matthew G.
AU - Thomas, Craig
AU - Staudt, Louis M.
AU - Zenz, Thorsten
AU - Oellerich, Thomas
N1 - Funding Information:
This work was supported in part by research funding from the Else-Kroener-Fresenius Foundation (A.C.W.); grants from the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) (SCHE 2120/1-1 [S.S.]), (Project-ID 259130777 – SFB 1177 [T.O.]) (RE 2246/13-1 [H.C.R.]), and (GO 2688/1-1 | SCHM 1633/11-1, SCHM 1633/9-1 [C.A.S.]); the German Cancer Aid (Deutsche Krebshilfe) (grant no. 70113536 [T.O.]), (grant nos. 1117240, 70113041, 70114055 [H.C.R.]), (grant no. 7011377629 [C.A.S.]); from the German-Israeli Foundation for Research and Development (I-65-412.20-2016) and the Deutsche Jose Carreras Leukämie Stiftung (R12/08) (H.C.R.); the German Ministry of Education and Research (BMBF) (e:Med 01ZX1303A [H.C.R.]) and (e:Med, project SeneSys, 031L0189A [C.A.S.]); and faculty scholars award from HHMI, SU2C, the MIT Center for Precision Cancer Medicine, the Ludwig Center at MIT, and the National Cancer Institute grant no. R35CA242379 [M.G.V.H.]. Y.P. is supported by National Cancer Institute K08 CA222684 and Hyundai Hope on Wheels grant.
Funding Information:
The authors thank the Microarray and High Throughput Sequencing unit of the DKFZ Genomics Core Facility and the Whitehead Institute Metabolite Profiling Core Facility for their services. The authors also thank Adam Friedman, Feng Zhang, Johannes Zuber, and Didier Trono for providing reagents and Silvia M?nch, Uwe Plessmann, Monika Raabe, Martine Pape, Samira Hitschler, and Jennifer Appelhans for their technical support. The authors thank the GMALL study group for providing patient samples. This work was supported in part by research funding from the Else-Kroener-Fresenius Foundation (A.C.W.); grants from the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) (SCHE 2120/1-1 [S.S.]), (Project-ID 259130777 ? SFB 1177 [T.O.]) (RE 2246/13-1 [H.C.R.]), and (GO 2688/1-1 | SCHM 1633/11-1, SCHM 1633/9-1 [C.A.S.]); the German Cancer Aid (Deutsche Krebshilfe) (grant no. 70113536 [T.O.]), (grant nos. 1117240, 70113041, 70114055 [H.C.R.]), (grant no. 7011377629 [C.A.S.]); from the German-Israeli Foundation for Research and Development (I-65-412.20-2016) and the Deutsche Jose Carreras Leuk?mie Stiftung (R12/08) (H.C.R.); the German Ministry of Education and Research (BMBF) (e:Med 01ZX1303A [H.C.R.]) and (e:Med, project SeneSys, 031L0189A [C.A.S.]); and faculty scholars award from HHMI, SU2C, the MIT Center for Precision Cancer Medicine, the Ludwig Center at MIT, and the National Cancer Institute grant no. R35CA242379 [M.G.V.H.]. Y.P. is supported by National Cancer Institute K08 CA222684 and Hyundai Hope on Wheels grant.
Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/1/27
Y1 - 2022/1/27
N2 - 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.
AB - 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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U2 - 10.1182/blood.2021012081
DO - 10.1182/blood.2021012081
M3 - Article
C2 - 34624079
AN - SCOPUS:85123713626
SN - 0006-4971
VL - 139
SP - 538
EP - 553
JO - Blood
JF - Blood
IS - 4
ER -