Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1) deficiency

Nademi, Zohreh; Wynn, Robert; Slatter, Mary; Hughes, Stephen; Bonney, Denise; Qasim, Waseem; Latour, Sylvain; Trück, Johannes; Patel, Smita Y.; Abinun, Mario; Flood, Terry; Hambleton, Sophie; Cant, Andrew J.; Gennery, Andrew R.; Arkwright, Peter D.

doi:10.1038/s41409-018-0246-x

Cited by 15 publications

(14 citation statements)

References 7 publications

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“…Hematopoietic stem cell transplantation (HSCT) was performed in 15 of the 19 patients. Thirteen out of 15 are alive and well at the most recent follow-up (17). Two patients died from severe viral infection (P3.1 and P5) before HSCT could be performed, and 2 (P12 and P13) are alive and have yet to receive transplants.…”

Section: Resultsmentioning

confidence: 97%

“…These data were similar to those reported previously for CTPS1-deficient patients. (6,(15)(16)(17). Ranges and numbers of the different blood cell populations were compared to established healthy pediatric standards (18)(19)(20)(21).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we and others identified immunodeficient patients with a CTPS1 deficiency leading to mainly life-threatening herpes virus infections with varicella-zoster virus (VZV) and EBV. All patients characterized so far have been shown to carry the same homozygous mutation IVS18-1 G>C or NM_001905.3: c.1692-1G>C, p.T566Dfs26X (rs145092287) in the acceptor splice site at introns 17-18, with a likely common ancestor from northwest England (6,(15)(16)(17). In our initial study, we showed that CTPS1 is important for the expansion of activated T cells.…”

Section: Introductionmentioning

confidence: 86%

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Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation

Martin¹,

Minet²,

Boschat³

et al. 2020

JCI Insight

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

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Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation

Martin¹,

Minet²,

Boschat³

et al. 2020

JCI Insight

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“…CTPS1 immunodeficiency results from a founder homozygous mutation in CTPS1 , and was originally identified among a population in the north‐west England . Eighteen affected patients have been identified to date (Martin, E. and Latour, S., unpublished data). All the patients experienced recurrent bacterial and viral infections, and most had a severe EBV infection (associated with the occurrence of B‐cell lymphoma in two cases).…”

Section: Immunodeficiencies Causing Ebv‐driven B‐lymphoproliferative mentioning

confidence: 99%

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Latour

Fischer

2019

Immunological Reviews

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113

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Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV -notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T-and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions. K E Y W O R D S B-cell lymphoproliferation, cell-cytotoxicity, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, primary immunodeficiency, T-cell proliferation | IMMUNE RE S P ON S E S TO EBV INFEC TI ONEpstein-Barr virus (EBV, also known as human herpesvirus 4) is a gamma herpes virus that only infects primates (primarily humans). 1,2 It is an encapsidated, double-stranded DNA virus with more than 100 genes. It is pandemic, since the great majority of human beings (>90%) have been infected by EBV. The main cell target is B lymphocytes that express CD21 -the membrane receptor for EBV entry through its 350 kDa major envelope glycoprotein. In immunocompetent adolescents and adults, EBV infection causes infectious mononucleosis (IM). Immunologically speaking, IM is characterized by a This article is part of a series of reviews covering Signaling and Signal Diversification in Immune

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“…Most CTPS1 deficient patients experienced EBV disease, including severe infectious mononucleosis, chronic EBV viremia and EBV-associated primary CNS lymphomas (16). Extra-hematopoietic manifestations of CTPS1 deficiency have not been reported, and hematopoietic stem cell transplantation is curative (17).…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival

Liang

Wang

Yiu

et al. 2021

Preprint

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Epstein-Barr virus (EBV) is associated with 200,000 cancers annually, including B-cell lymphomas in immunosuppressed hosts. Hypomorphic mutations of the de novo pyrimidine synthesis pathway enzyme cytidine 5’ triphosphate synthase 1 (CTPS1) suppress cell mediated immunity, resulting in fulminant EBV infection and EBV+ central nervous system (CNS) lymphomas. Since CTP is a critical precursor for DNA, RNA and phospholipid synthesis, this observation raises the question of whether the isozyme CTPS2 or cytidine salvage pathways help meet CTP demand in EBV-infected B-cells. Here, we found that EBV upregulated CTPS1 and CTPS2 with distinct kinetics in newly infected B-cells. While CRISPR CTPS1 knockout caused DNA damage and proliferation defects in lymphoblastoid cell lines (LCL), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC and non-canonical NF-□B positively regulated CTPS1 expression. CTPS1 depletion impaired EBV lytic DNA synthesis, suggesting that latent EBV may drive pathogenesis with CTPS1 deficiency. Cytidine rescued CTPS1/2 deficiency phenotypes in EBV-transformed LCL and Burkitt B-cells, highlighting CTPS1/2 as a potential therapeutic target for EBV-driven lymphoproliferative disorders. Collectively, our results suggest that CTPS1 and CTPS2 have partially redundant roles in EBV-transformed B-cells and provide insights into EBV pathogenesis with CTPS1 deficiency.

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Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1) deficiency

Abstract: CTPS1 deficiency causes early onset herpes virus infections particularly with VZV and EBV and there is a high risk of developing lymphoma. We report eleven patients treated by hematopoietic stem cell transplantation, eight of whom survived with resolution of symptoms.

Cited by 15 publications

References 7 publications

Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation

Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival

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