AML malignant mechanism by enhancer reprogramming of Trib1

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16318
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Nagoya University (2021); Japanese Foundation for Cancer Research (2020)
• Principal Investigator: Yoshino Seiko 名古屋大学, 医学系研究科, 特任助教 (40793617)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: Trib1 / Hoxa9 / ChIP-seq / 白血病 / Ts1Cje / ダウン症関連白血病

Outline of Final Research Achievements

Down syndrome is caused by trisomy of chromosome 21 and is the most frequent genetic disorder arising from chromosomal abnormality. Trib1 pseudokinase acts as a collaborator of Hoxa9/Meis1 in leukemogenesis, inducing enhancement of MAPK signals and degradation of C/EBPa. Ts1Cje, a mouse model for DS, is trisomic for approximately 70 genes of human chromosome 21. Here, we aimed to introduce Trib1 in Ts1Cje mice to examine whether the expression of Trib1 cooperates with trisomy 21 in the development of leukemia. Expression of both wild type and R107L Trib1 in Ts1Cje bone marrow cells significantly accelerated disease onset of AML. Additionaly, AML cell lines expressing wild type Trib1 were generated in Ts1Cje and B6 bone marrow cells. Gene set enrichment analysis showed the enrichment of the target gene sets of the posterior Hoxa cluster. These data strongly suggest the importance of TRIB1-associated signaling in the transformation and/or malignant progression of DS-related leukemia.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究により、Trib1の発現の有無で変動するエンハンサーおよびスーパーエンハンサーとエンハンサーに集積する新規転写因子群が明らかになった。今後は、これら転写因子群が正の制御ループを形成し、Trib1によるAML悪性化機構に関与するのかどうかを検証する。さらに、Trib1はダウン症モデルマウスのAML発症を促進し、Trib1を発現するTs1Cje細胞は、野生型細胞と比較して、Hoxa標的遺伝子群の発現がエンリッチしていることが明らかになった。Trib1の関連するシグナルがダウン症関連白血病の悪性化に寄与していることから、TRIB1が治療標的になる可能性が示唆された。