Development of a novel treatment toward prevention of HTLV-1 transmission and ATL disease onset

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17402
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokushima
• Principal Investigator: HARADA Takeshi 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (10618359)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 成人T細胞白血病リンパ腫 / NF-kB / PIM1

Outline of Final Research Achievements

Adult T cell leukemia/lymphoma (ATL) cells constitutively activate NF-kB signaling pathway. Inhibition of the signaling or gene suppression of the transcription factor (TF) RELA, which is the pivotal TF in the signaling, induced apoptosis and downregulated PIM1 expression in ATL cells. PIM1 suppression/ a PIM inhibitor PIM447 induced apoptosis and downregulated RelA and TF c-MYB in protein levels but not mRNA levels. Puromycin incorporation assay demonstrated that PIM-kinase inhibition blocked translation in ATL cells. Furthermore, an Akt inhibitor MK-2206 cooperatively induced cytotoxicity in combination with PIM447 against ATL cells, suggesting PIM kinases and PI3K/Akt signaling both regulate a protein synthesis axis in ATL cells. Taken together, our findings are further warranted on the effect of blockade of protein synthesis for the prevention of ATL disease onset and HTLV-1 transmission.

Free Research Field

血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

NF-kB経路とPIM1の関係を中心にATLに対する治療標的の探索を行い、PIM阻害薬とAkt阻害薬によるタンパク質合成経路の阻害が、ATL細胞において、NF-kB経路の制御因子を含む転写因子の発現を低下させ、アポトーシスを誘導できる結果を見出した。本研究成果は、ATL研究において未だ未開発で、ATL治療開発を促進できる可能性があり、学術的意義は大きい。また、HTLV-1ウイルス感染伝播やATL発症に関する研究にも裾野を拡げていく予定であり、社会的意義は今後大きくなると期待できる。