Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. SHMT2 localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of SHMT2 cooperates with BCL2 in lymphoma development; loss or inhibition of SHMT2 impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support S-adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as SASH1 and PTPRM. Together, our findings reveal that amplification of SHMT2 in cooperation with BCL2 is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.
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Sequencing (RNA-seq, proton sequencing, ChIP–seq and ERRBS) data that support the findings of this study have been deposited in the Gene Expression Omnibus under accession codes GSE142336 and GSE139523. Previously published microarray data that were reanalyzed in this study are available under accession code GSE132929. Histone mass spectrometry data were deposited to MassIVE under accession code MSV000085251. Source data for Figs. 1–7 and Extended Data Fig. 2 have been provided as Source Data Files 1–12. All other data supporting the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.
Any custom computer code or algorithm previously used to generate results that are reported in this paper and central to its main claims are available upon request.
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We thank R.L. Possemato (NYU) for sharing the pMXS-IRES-blast; SHMT2res and pMXS-IRES-blast; SHMT2-CD (SHMT2 K280A) plasmids, and T. Oellerich for sharing the lentiviral catalytic dead SHMT2 (SHMT2 K280A) plasmid. We thank Raze Therapeutics for sharing the SHIN1 drug. We thank K.R. Keshari, L.W.S. Finely, W. Beguelin and L. Cerchietti for helpful discussions and suggestions. We thank V. Sanghavi, K. Singh, D. Salloum and other members of Wendel laboratory for advice and reagents. Also, we thank V. Di Gialleonardo and C. Duy. We thank all members of the MSK Antitumor Assessment Core for technical assistance with the mice; the MSK Laboratory of Comparative Pathology and MSK Flow Cytometry for their support in processing biological samples; and the Weill Cornell Epigenomics Core for performing the RNA-seq, ERBBS and ChIP–seq. We acknowledge the use of the Integrated Genomics Operation Core, funded by an NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. This research was supported by funding from the National Institutes of Health (NIH) SPORE in Soft Tissue Sarcoma (grant no. P50 CA217694 to H.-G.W.), Starr Cancer Consortium (to H.-G.W. and B.-K), Technology Development Fund (grant no. GC230724 to H.-G.W.), Starr Cancer Consortium (grant no. I10-0064 to H.-G.W.), the Lymphoma Research Foundation (grant no. GC233089 to H.-G.W.), NIH grant nos. RO1CA183876-05, RO1CA207217-03, NIH Spore P50 CA192937-03, LLS 7014-17 and LLS 1318-15 (to H.-G.W.). H.-G.W. is a Scholar of the Leukemia and Lymphoma Society.
A.D. has received personal consultancy fees from Roche, Corvus Pharmaceuticals, Physicians’ Education Resource, Seattle Genetics, Takeda, EUSA Pharma and AbbVie, and research grants from Roche. The other authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a, Bar graphs presenting the functional gain (red) or loss (blue) of SHMT2 located on chromosome 12 by DNA copy number analysis of 568 DLBCL and 176 FL tumors. b, The frequency of loss (blue), gain (red) or diploid (black) status of serine synthesis pathway genes in 568 human DLBCL and 176 human FL tumors. c, Diagrams demonstrating the overlaps of amplification (red) and loss (blue) of SHMT2 vs other serine biosynthesis pathway enzymes (PSPH, PHGDH, PSAT1, SHMT1) in 568 DLBCL and 176 FL tumors. d, Bar graph showing the frequency of SHMT2 amplification in different subtype (GC-like, ABC-like or unclassified) of 249 human DLBCL tumors.
a, Diagram of FL mouse model. Fetal VavPBcl2 HSCs were transduced by MSCV-GFP plasmid carrying SHMT2 cDNA or empty vector and injected to lethally irradiated female mice. b, Representative graphs of flow cytometry analysis comparing GFP+ HSCs before injection vs GFP+ splenic lymphoma cells from VavPBcl2;vector- and VavPBcl2;SHMT2- induced tumors collected 5 months after injection. c, Dot plot representing the initial GFP+ cells in hematopoietic stem cells before injection vs GFP+ cells enriched in splenic cells collected from VavP-Bcl2;vector (N = 5 mice) and VavP-Bcl2;SHMT2 (N = 10 mice) tumors. Two-tailed Student’s t-test was used to determine statistical significance; VavP-Bcl2;vector: P(HSCvsLymphoma)= 0.443, NS; VavP-Bcl2;SHMT2: P(HSCvsLymphoma)=0.0006. d, Representative images of histology studies of VavPBcl2;vector and VavPBcl2;SHMT2 lung. The slides were stained with H&E, and antibodies for B220, TUNEL, Ki67, PNA. This experiment was independently repeated three times with similar results. Scale Bars, 500 nm. e, tumor clonality analysis on B220+ cDNA collected from VavPBcl2;vector vs VavPBcl2;SHMT2 tumors. Each lane corresponds to one tumor. This experiment was independently repeated two times with four independent samples in each genotype with similar results f, Immunoblot against SHMT2, SHMT1 and ACTIN in DLBCL cell lines carrying two different short hairpins against SHMT2. This experiment was independently repeated two times with similar results. The uncropped images of the original blots are presented in Source Data Extended Data File 12. The numerical data for this figure are presented in Source Data Extended Data File 2.
Numerical data for Fig. 1.
Unprocessed western blots for Fig. 2b.
Numerical data for Fig. 2.
Histological micrographs and flow cytometry analysis of replicates in Fig. 2e,f.
Unprocessed western blots for Fig. 3j.
Numerical data for Fig. 3.
Unprocessed western blots for Fig. 4g.
Numerical data for Fig. 4.
Flow cytometry analysis of replicates in Fig. 4b,f.
Numerical data for Fig. 5.
Unprocessed dot blots for Fig. 5.
Numerical data for Fig. 6.
Histological micrographs and flow cytometry analysis of replicates in Fig. 7.
Numerical data for Fig. 7.
Unprocessed western blots for Extended Data Fig. 2.
Numerical data for Extended Data Fig. 2.
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Parsa, S., Ortega-Molina, A., Ying, HY. et al. The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing. Nat Cancer 1, 653–664 (2020). https://doi.org/10.1038/s43018-020-0080-0
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