SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma

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

doi:10.1182/blood.2021012081

SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma

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. CoulibalySebastian 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

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Pages (from-to)	538-553
Number of pages	16
Journal	Blood
Volume	139
Issue number	4
DOIs	https://doi.org/10.1182/blood.2021012081
State	Published - Jan 27 2022
Externally published	Yes

All Science Journal Classification (ASJC) codes

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood.2021012081

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Wilke, A. C., Doebele, C., Zindel, A., Lee, K. S., Rieke, S. A., Ceribelli, M., Comoglio, F., Phelan, J. D., Wang, J. Q., Pikman, Y., Jahn, D., Häupl, B., Schneider, C., Scheich, S., Tosto, F. A., Bohnenberger, H., Stauder, P., Schnütgen, F., Slabicki, M., ... Oellerich, T. (2022). SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma. Blood, 139(4), 538-553. https://doi.org/10.1182/blood.2021012081

@article{6fc0e21ef64e4f53af773bb7e6f6af37,

title = "SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma",

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.",

author = "Wilke, {Anne C.} and Carmen Doebele and Alena Zindel and Lee, {Kwang Seok} and Rieke, {Sara A.} and Michele Ceribelli and Federico Comoglio and Phelan, {James D.} and Wang, {James Q.} and Yana Pikman and Dominique Jahn and Bj{\"o}rn H{\"a}upl and Constanze Schneider and Sebastian Scheich and Tosto, {Frances A.} and Hanibal Bohnenberger and Philipp Stauder and Frank Schn{\"u}tgen and Mikolaj Slabicki and Coulibaly, {Zana A.} and Sebastian Wolf and Kamil Bojarczuk and Bj{\"o}rn Chapuy and Brandts, {Christian H.} and Philipp Stroebel and Lewis, {Caroline A.} and Michael Engelke and Xincheng Xu and Hahn Kim and Dang, {Thanh Hung} and Roland Schmitz and Hodson, {Daniel J.} and Kimberly Stegmaier and Henning Urlaub and Hubert Serve and Schmitt, {Clemens A.} and Fernando Kreuz and Gero Knittel and Rabinowitz, {Joshua D.} and Reinhardt, {Hans Christian} and {Vander Heiden}, {Matthew G.} and Craig Thomas and Staudt, {Louis M.} and Thorsten Zenz and Thomas Oellerich",

note = "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 Leuk{\"a}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. 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: {\textcopyright} 2022 American Society of Hematology",

year = "2022",

month = jan,

day = "27",

doi = "10.1182/blood.2021012081",

language = "English (US)",

volume = "139",

pages = "538--553",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "4",

}

Wilke, AC, Doebele, C, Zindel, A, Lee, KS, 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, TH, Schmitz, R, Hodson, DJ, Stegmaier, K, Urlaub, H, Serve, H, Schmitt, CA, Kreuz, F, Knittel, G, Rabinowitz, JD, Reinhardt, HC, Vander Heiden, MG, Thomas, C, Staudt, LM, Zenz, T & Oellerich, T 2022, 'SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma', Blood, vol. 139, no. 4, pp. 538-553. https://doi.org/10.1182/blood.2021012081

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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UR - http://www.scopus.com/inward/citedby.url?scp=85123713626&partnerID=8YFLogxK

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 -

SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma

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