Trib1 functions as a critical epigenetic regulator in AML

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15227
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Yoshino Seiko 公益財団法人がん研究会, がん研究所 発がん研究部, 研究員 (40793617)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: Trib1 / Hoxa9 / C/EBPα / ChIP-seq / 白血病

Outline of Final Research Achievements

The pseudokinase Trib1 functions as a myeloid oncogene that recruits the ubiquitin ligase COP1 to C/EBPα and interacts with MEK1 to enhance ERK phosphorylation. Close genetic interaction between Trib1 and Hoxa9 have been observed in myeloid leukemogenesis. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analysis identified increased H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased mRNA expression. Modification of super-enhancer activity was mostly achieved via p42-specific degradation of C/EBPα by Trib1. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target. Moreover, treatment with a BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Collectively, our study demonstrates a novel mechanism of Trib1 in modulations of chromatin and Hoxa9-driven transcription.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

Trib1は、野生型の骨髄幹／前駆細胞での過剰発現だけで細胞の不死化とin vivoでの白血病誘導能を示す数少ない白血病原因遺伝子である。本研究は、Trib1を軸として、これまで繋がりが見えなかったHoxa9とC/EBPαのクロストークを明らかにした。さらに、本研究で同定した、Trib1/Hoxa9標的遺伝子が、新たな治療標的やバイオマーカーの発見に結びつくことが期待できる。