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

Parsa, Sara; Ortega-Molina, Ana; Ying, Hsia-Yuan; Jiang, Man; Teater, Matt; Wang, Jiahui; Zhao, Chunli; Reznik, Ed; Pasion, Joyce; Kuo, David; Mohan, Prathibha; Wang, Shenqiu; Camarillo, Jeannie M.; Thomas, Paul M.; Jain, Neeraj; García‐Bermúdez, Javier; Cho, Byoung-kyu; Kelleher, Neil L.; Socci, Nicholas D.; Doğan, Ahmet; Stanchina, Elisa de; Ciriello, Giovanni; Green, Michael R.; Li, Sheng; Birsoy, Kıvanç; Melnick, Ari; Wendel, Hans-Guido

doi:10.1038/s43018-020-0080-0

Cited by 45 publications

(40 citation statements)

References 58 publications

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“…In assays of cell growth, SHMT1 overexpression did not rescue the suppressive phenotype resulting from SHMT2 loss in Rh30 cells (Supplemental Figure 5B). This finding is consistent with previous reports that expression of SHMT2, but not SHMT1, is important for cell growth and proliferation of lymphoma (21,22), hepatocellular carcinoma (23) and colorectal cancer cells (24).…”

Section: Knockdown Of Shmt2 Suppresses Cell Growth and Tumor Formationsupporting

confidence: 93%

“…As described above, these SHMT2-containing amplicons also exist in the TCGA lung cancer dataset used in our analysis but were not sufficiently common to be included in the high confidence amplified region. Finally, it should be noted that SHMT2 amplification has recently been reported in lymphoma (22) and overexpression has been reported in several other cancer types (21,23,24), but the relationship to DNA copy number changes has not been determined.…”

Section: Discussionmentioning

confidence: 99%

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Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification

Nguyen¹,

Vemu²,

Hoy³

et al. 2021

Journal of Clinical Investigation

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The 12q13-q14 chromosomal region is recurrently amplified in 25% of fusion-positive (FP) rhabdomyosarcoma (RMS) cases and is associated with a poor prognosis. To identify amplified oncogenes in FP RMS, we compared the size, gene composition and expression of 12q13-q14 amplicons in FP RMS with other cancer categories (glioblastoma multiforme, lung adenocarcinoma and liposarcoma) in which 12q13-q14 amplification frequently occurs. We uncovered a 0.2 Mb region that is commonly amplified across these cancers and includes CDK4 and six other genes that are overexpressed in amplicon-positive samples. Additionally, we identified a 0.5 Mb segment that is only recurrently amplified in FP RMS and includes four genes that are overexpressed in amplicon-positive RMS. Among these genes, only SHMT2 was overexpressed at the protein level in an amplicon-positive RMS cell line. SHMT2 knockdown in ampliconpositive RMS cells suppressed growth, transformation and tumorigenesis, whereas overexpression in amplicon-negative RMS cells promoted these phenotypes. High SHMT2 expression reduced sensitivity of FP RMS cells to SHIN1, a direct SHMT2 inhibitor, but sensitized cells to pemetrexed, an inhibitor of the folate cycle. In conclusion, our study demonstrated that SHMT2 contributes to tumorigenesis in FP RMS and that SHMT2 amplification predicts differential response to drugs targeting this metabolic pathway.

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Section: Knockdown Of Shmt2 Suppresses Cell Growth and Tumor Formationsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification

Nguyen¹,

Vemu²,

Hoy³

et al. 2021

Journal of Clinical Investigation

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“…The modulation of SAM availability was also proposed to mediate the effect of the overexpression of a wild type metabolic enzyme, namely SHMT2, in driving oncogenesis in B-cell lymphoma 2 (BCL2)-expressing lymphomas. Overexpression of SHMT2, which is implicated in serine catabolism, led to epigenetic repression of the tumor suppressor genes encoding SAM and SH3 domain containing 1 (SASH1) and protein tyrosine phosphatase receptor type M (PTPRM), driving lymphomagenesis [101].…”

Section: Metabolic Effects On Epigeneticsmentioning

confidence: 99%

From the (Epi)Genome to Metabolism and Vice Versa; Examples from Hematologic Malignancy

Karagianni

Giannouli

Voulgarelis

2021

IJMS

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Hematologic malignancies comprise a heterogeneous group of neoplasms arising from hematopoietic cells or their precursors and most commonly presenting as leukemias, lymphomas, and myelomas. Genetic analyses have uncovered recurrent mutations which initiate or accumulate in the course of malignant transformation, as they provide selective growth advantage to the cell. These include mutations in genes encoding transcription factors and epigenetic regulators of metabolic genes, as well as genes encoding key metabolic enzymes. The resulting alterations contribute to the extensive metabolic reprogramming characterizing the transformed cell, supporting its increased biosynthetic needs and allowing it to withstand the metabolic stress that arises as a consequence of increased metabolic rates and changes in its microenvironment. Interestingly, this cross-talk is bidirectional, as metabolites also signal back to the nucleus and, via their widespread effects on modulating epigenetic modifications, shape the chromatin landscape and the transcriptional programs of the cell. In this article, we provide an overview of the main metabolic changes and relevant genetic alterations that characterize malignant hematopoiesis and discuss how, in turn, metabolites regulate epigenetic events during this process. The aim is to illustrate the intricate interrelationship between the genome (and epigenome) and metabolism and its relevance to hematologic malignancy.

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“…Nucleotide synthesis represents another therapeutic vulnerability in lymphomas, as evidenced by the long-standing use of methotrexate and pralatrexate in these diseases. Targeted inhibition of serine hydroxymethyltransferases 1 and 2 (SHMT1/2), key enzymes in serine-driven one-carbon folate metabolism, impeded purine biosynthesis, disrupted DNA/histone methylation, and arrested B-cell lymphoma proliferation; concurrent glycine restriction and/or inhibition of glycine uptake augmented this ef-fect (Ducker et al 2017;Parsa et al 2020). EBVdriven lymphomas exhibit increased uptake of serine and glycine and enhanced metabolic flux through the one-carbon folate pathway for nucleotide biosynthesis (Wang et al 2019b(Wang et al , 2019c.…”

Section: Nucleotidesmentioning

confidence: 99%

Oncogenic Mechanisms and Therapeutic Targeting of Metabolism in Leukemia and Lymphoma

Stahl

Epstein‐Peterson

Intlekofer

2020

Cold Spring Harb Perspect Med

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Leukemias and lymphomas acquire the capacity for unrestrained cell growth and proliferation in conjunction with loss of responsiveness to molecular programs that promote terminal differentiation. Malignant cells generate the building blocks required for rapid cell division through both increased acquisition of nutrients from the environment and reprogrammed intermediary metabolism to shunt these molecules into producing the protein, lipids, and nucleic acids that comprise cell biomass. These accelerated metabolic processes require energy in the form of ATP and reducing equivalents in the form of NADPH, which power biosynthetic reactions and buffer oxidative stress encountered by the metabolically active cancer cell. Cancer-associated metabolic alterations can also promote accumulation or depletion of specific metabolites that directly regulate cell fate and function, thereby coupling metabolic reprogramming to dedifferentiation and stemness. This review will focus on the mechanisms by which leukemia and lymphoma cells rewire cellular metabolism to support:(1) bioenergetics, (2) biomass accumulation, (3) redox balance, and (4) differentiation blockade. We will further highlight examples of how specific pathways of leukemia and lymphoma metabolism confer therapeutic vulnerabilities that can be targeted to inhibit growth or promote differentiation.A t a fundamental level, cancer is a problem of hijacked cellular metabolism (Vander Heiden et al. 2009). Normally, metazoan cells require "permission" from growth factors, cytokines, hormones, or antigen/costimulatory receptors to increase nutrient uptake. All cancers, including leukemias and lymphomas, acquire the capacity for cell-autonomous uptake of nutrients that circumvents normal regulatory mechanisms (Palm and Thompson 2017). Such unrestricted nutrient uptake is critical to build the cellular biomass ( protein, lipids, nucleic acids) necessary for rapid cell doubling (Fig. 1). Because the availability of specific nutrients in the environment does not precisely match the necessary outputs, cancer cells must rewire metabolic circuits to rapidly convert available nutrients into precursor metabolites

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

Cited by 45 publications

References 58 publications

Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification

Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification

From the (Epi)Genome to Metabolism and Vice Versa; Examples from Hematologic Malignancy

Oncogenic Mechanisms and Therapeutic Targeting of Metabolism in Leukemia and Lymphoma

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