Elucidation of the mechanism of ATLL development and identification of leukemic stem cell profiles using a mouse model

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08715
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Kameda Takuro 宮崎大学, 医学部, 助教 (30468029)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ATLL / HBZ / CARD11 / 癌 / シグナル伝達 / ウイルス

Outline of Final Research Achievements

We analyzed mice transfected with the viral gene HBZ (HBZ TG), mice transfected with a CARD11 mutation that activates the TCR-NFκB pathway (CARD11mut TG), and mice with a combination of these abnormalities (compound TG). HBZ TG and CARD11mut TG cause a slow onset of lymphoproliferative disease, and compound TG causes a rapid onset of lymphoproliferative disease with T cell infiltration of organs, and that these mouse models recapitulate ATL pathology.
Compound TG showed increased expression of a variety of proliferation-related gene sets and recapitulated approximately 80% of the aberrant gene sets found in human acute type ATL specimens, suggesting that NFκB activation associated with mutations in TCR-NFκB pathway molecules and expression of the viral gene HBZ form the molecular basis of ATL.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

HBZ TG、CARD11変異TG、二重異常TGの各マウスの解析から、ATLの分子病態を明らかにした（Communications Biology. Kameda et al. 2022）。二重異常TGマウスでは、ATL検体と類似したTCR/NF-κB経路の活性化と、生後半年でのリンパ増殖性疾患の発症が観察され、また、CD4 T cellにおいてはヒトATL検体と類似した遺伝子発現異常が観察されたことから、ATLの基本的な分子病態の形成機序が明らかになった。今後、分子病態に即した新規治療の開発が期待される。