Article ; Online: Reprogramming of pyrimidine nucleotide metabolism supports vigorous cell proliferation of normal and malignant T cells.
2024 Volume 8, Issue 6, Page(s) 1345–1358
Abstract: Abstract: Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine- ... ...
| Abstract | Abstract: Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine-cytidine kinase 2 (UCK2), which supports vigorous proliferation. UCK2 catalyzes the monophosphorylation of cytidine/uridine and their analogues during pyrimidine biosynthesis and drug metabolism. We found that UCK2 was overexpressed aberrantly in HTLV-1-infected T cells but not in normal T cells. T-cell activation via T-cell receptor (TCR) signaling induced expression of UCK2 in normal T cells. Somatic alterations and epigenetic modifications in ATL cells activate TCR signaling. Therefore, we believe that expression of UCK2 in HTLV-1-infected cells is induced by dysregulated TCR signaling. Recently, we established azacitidine-resistant (AZA-R) cells showing absent expression of UCK2. AZA-R cells proliferated normally in vitro, whereas UCK2 knockdown inhibited ATL cell growth. Although uridine and cytidine accumulated in AZA-R cells, possibly because of dysfunction of pyrimidine salvage biosynthesis induced by loss of UCK2 expression, the amount of UTP and CTP was almost the same as in parental cells. Furthermore, AZA-R cells were more susceptible to an inhibitor of dihydroorotic acid dehydrogenase, which performs the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, and more resistant to dipyridamole, an inhibitor of pyrimidine salvage biosynthesis, suggesting that AZA-R cells adapt to UCK2 loss by increasing de novo pyrimidine nucleotide biosynthesis. Taken together, the data suggest that fine-tuning pyrimidine biosynthesis supports vigorous cell proliferation of both normal T cells and ATL cells. |
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| MeSH term(s) | Adult ; Humans ; Pyrimidines ; Uridine/metabolism ; Cell Proliferation ; Cytidine ; Human T-lymphotropic virus 1 ; Pyrimidine Nucleotides ; Receptors, Antigen, T-Cell ; T-Lymphocytes/metabolism |
| Chemical Substances | Pyrimidines ; Uridine (WHI7HQ7H85) ; Cytidine (5CSZ8459RP) ; Pyrimidine Nucleotides ; Receptors, Antigen, T-Cell |
| Language | English |
| Publishing date | 2024-01-08 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 2915908-8 |
| ISSN | 2473-9537 ; 2473-9529 |
| ISSN (online) | 2473-9537 |
| ISSN | 2473-9529 |
| DOI | 10.1182/bloodadvances.2023011131 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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