2022 Fiscal Year Final Research Report
Biological significance of DNA methylation abnormalities in ATL leukemogenesis
| Project/Area Number |
20K07593
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Saga University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
末岡 榮三朗 佐賀大学, 医学部, 教授 (00270603)
服部 奈緒子 国立研究開発法人国立がん研究センター, 研究所, 研究員 (30611090)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | ATL / DNA methylation / Acquired resistance / Pyrimidine metabolism / Methionine metabolism / DNA demethylating agents |
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| Outline of Final Research Achievements |
Adult T-cell leukemia lymphoma is a highly malignant T-cell malignancy caused by HTLV-1 infection. Since DNA hypermethylation is linked to leukemogenesis in ATL, DNA hypomethylation by DNA demethylating agents is a possible therapeutic approach. Here, we found that reconstitution of THEMIS, whose expression was silenced in ATL cells by promoter hypermethylation, inhibited tumor cell growth in axillary lymph nodes in a xenograft mouse model which subcutaneously inoculated with ATL cells. Furthermore, we revealed that down-regulated expression of the pyrimidine metabolism enzymes UCK2 and DCK correlates with acquired resistance to azacitidine and decitabine, respectively. Methionine restriction suppressed the growth of HTLV-1-infected cell lines with DNA hypomethylation in vitro. The expression of SLC7A5 which acts as a methionine transporter, was induced in tissue samples from patients with ATL, suggesting that methionine metabolism is related to DNA hypermethylation in ATL cells.
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| Free Research Field |
血液腫瘍学
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| Academic Significance and Societal Importance of the Research Achievements |
成人T細胞白血病・リンパ腫(ATL)は原因であるHTLV-1の感染から数十年の潜伏期間を経てごく一部の感染者で発症する極めて予後不良の血液腫瘍であり、効果的な治療法や発症予防、病態の進展予防法の開発が望まれている。本研究において、DNA脱メチル化薬を用いた治療が開始された際に問題となる耐性化細胞の出現について、その分子機構を予め理解することが出来た。また、ATL細胞で特徴的なエピゲノム異常について、新たにメチオニン代謝の関与を明らかにしたことから、既存の対処療法では無く、メチオニン代謝を標的にした、新しいATL治療、あるいは予防法の開発の足掛かりとなる成果を得た。
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