Mechanisms of aberrant DNA replication in adult T-cell leukemia/lymphoma

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K14988
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: University of the Ryukyus
• Principal Investigator: Mizuguchi Mariko 琉球大学, 医学(系)研究科(研究院), 助教 (40581541)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: HTLV-1 / ATL / DNA複製

Outline of Final Research Achievements

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type-1 (HTLV-1) infection. Although an accumulation of genetic mutation is seen in primary ATL cells, progression mechanisms remain unclear. From RNA sequencing analysis, we identified various genes involved in DNA replication and repair of DNA double-strand break through homologous recombination induced by oncogenic protein Tax1, and not by TaxM22, which lacks ability of NF-κB activation. Treatment of ATM and ATR inhibitors significantly increased apoptosis in Tax1-expressing cells. Our results suggest that Tax1-induced aberrant DNA replication and DNA double-strand break through NF-κB/RelA may be implicated in accumulation of genetic mutation in HTLV-1-infected cells.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

ATLは抗がん剤治療による寛解後でも高率に再発するため、新規治療薬の開発が求められている。ATLは多数の遺伝子変異が蓄積した結果、発症すると考えられており、HTLV-1感染細胞内で遺伝子変異が起こる分子メカニズムを明らかにすることは、それら分子を標的とした治療法の開発に貢献できると考えている。