The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing

Nat Cancer. 2020;1:653-664. doi: 10.1038/s43018-020-0080-0.

Sara Parsa ^# ¹, Ana Ortega-Molina ^# ¹, Hsia-Yuan Ying ², Man Jiang ¹, Matt Teater ², Jiahui Wang ³, Chunying Zhao ¹, Ed Reznik ⁴, Joyce P Pasion ¹, David Kuo ⁵, Prathibha Mohan ¹, Shenqiu Wang ¹, Jeannie M Camarillo ⁶, Paul M Thomas ⁶, Neeraj Jain ⁷ ⁸, Javier Garcia-Bermudez ⁹, Byoung-Kyu Cho ⁶, Wayne Tam ¹⁰, Neil L Kelleher ⁶, Nicholas Socci ¹, Ahmet Dogan ¹¹, Elisa De Stanchina ¹, Giovanni Ciriello ¹² ¹³, Michael R Green ⁷ ⁸, Sheng Li ³, Kivanc Birsoy ⁹, Ari M Melnick ², Hans-Guido Wendel ¹⁴

Affiliations

1 Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
2 Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, NY, USA.
3 The Jackson Laboratory Cancer Center, Farmington, CT, USA.
4 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
5 Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
6 Department of Chemistry, Molecular Biosciences and the National Resource for Translational and Developmental Proteomics, Northwestern University, Evanston, IL, USA.
7 Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8 Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9 Laboratory of Metabolic Regulation and Genetics, Rockefeller University, New York, NY, USA.
10 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
11 Hematopathology Service, Departments of Pathology and Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
12 Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
13 Swiss Institute of Bioinformatics, Lausanne, Switzerland.
14 Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. wendelh@mskcc.org.
# Contributed equally.

PMID: 33569544 DOI: 10.1038/s43018-020-0080-0

Abstract

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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