Exploring the link between serine metabolism and epigenetics in lymphoma Project description Follicular lymphoma (FL) is the second most common form of lymphoma and remains incurable despite advances against other forms of lymphoma. We noticed that ~30% of FL (and also DLBCLs) carry an amplification of the SHMT2 gene that encodes the enzyme serine hydroxymethyltransferase-2 - a key enzyme in serine metabolism. SHMT2 converts serine to glycine and this reaction yields activated methyl groups for biosynthetic and modification reactions including DNA and histone methylation. Serine metabolism has been implicated in cancer, for example PGHDH is amplified in breast cancer (Possemato et al. 2011, Beguelin et al. 2017), and SHMT2 levels correlate with proliferation across cancer cell lines (Ye et al. 2014). Lymphoma is, in large part, an epigenetic disease and we have characterized the most frequent causative mutations that affect epigenetic drivers such as KMT2D/MLL2, CREBBP/EP300, EZH2 and others (Kridel et al. 2012, Ortega-Molina et al. 2015, Jiang et al. 2017, Zhang et al. 2017). We speculate that aberrant serine catabolism is a driver of lymphoma biology and produces activated methyl groups that alter the epigenetic state of lymphoma cells. Our preliminary data support this new link between metabolism and epigenetics in lymphoma . For example, i) we find that SHMT2 acts as a driver of lymphoma development in a mouse model, ii) Metabolomics studies show increased production of S-adenosyl methionine (the donor of activated methyl groups) in SHMT2 driven lymphomas, and iii) human and murine SHMT2 amplified lymphomas show characteristic changes in DNA and histone methylation and gene expression. Based on these data we speculate that serine catabolism drives epigenetic modification and this contributes to lymphoma development in vivo. Moreover, aggressive lymphomas and cell lines depend on SHMT2 for growth and this requirement signals a potential therapeutic opportunity that we need to explore. In this project, we will explore the link between serine catabolism and epigenetics in a deadly form of lymphoma and we will test the potential for therapeutic intervention. !

Public Health Relevance

Follicular and Diffuse Large B Cell Lymphoma are the most common forms of B cell lymphoma and account for much morbidity and mortality. Epigenetic lesions are known drivers of these cancers. Serine catabolism is a target of copy number gains in FL and DLBCL and provide methyl groups for DNA and histone modifications. We will explore the link between serine metabolism and epigenetics in lymphoma. !

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Jhappan, Chamelli
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Sloan-Kettering Institute for Cancer Research
New York
United States
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